RESUMEN
Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.
Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).
Asunto(s)
Tumor de Células Gigantes de las Vainas Tendinosas , Humanos , Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Tumor de Células Gigantes de las Vainas Tendinosas/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.
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Antineoplásicos , Tumor de Células Gigantes de las Vainas Tendinosas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Receptor DCC , Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Tumor de Células Gigantes de las Vainas Tendinosas/patología , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras , Receptor de Factor Estimulante de Colonias de MacrófagosRESUMEN
Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-ß, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.
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Proteínas Tirosina Quinasas Receptoras , Urea , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Relación Estructura-Actividad , Urea/química , Urea/farmacologíaRESUMEN
A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Monitoreo de Drogas , Resistencia a Antineoplásicos/genética , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent FDA approval of covalent inhibitors of KRAS G12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRAS G12C -driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients that do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRAS G12C , efforts are underway to develop effective combination therapies. Here we report that inhibition of KRAS G12C signaling increases autophagy in KRAS G12C expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRAS G12C -driven lung cancer cell proliferation in vitro and superior tumor control in vivo . Additionally, in genetically engineered mouse models of KRAS G12C -driven NSCLC, inhibition of either KRAS G12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRAS G12C in lung cancer.
RESUMEN
An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti-programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34-dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti-tumor response. We showed that VPS34 inhibitors increased the secretion of T-cell-recruitment chemokines in a cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING)-dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)-mediated VPS34 inhibition increased cGAS/STING-mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16-F10 tumor-bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune-mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway.
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Fosfatidilinositol 3-Quinasas Clase III , Interferón Tipo I , Proteínas de la Membrana , Transducción de Señal , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/agonistas , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Ratones , Línea Celular Tumoral , Interferón Tipo I/metabolismo , Nucleotidiltransferasas/metabolismo , Ratones Endogámicos C57BL , Femenino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Conjugation to folic acid is known to enhance the uptake of molecules by human cells that over-produce folate receptors. Variants of bovine pancreatic ribonuclease (RNase A) that have attenuated affinity for the endogenous ribonuclease inhibitor protein (RI) are toxic to mammalian cells. Here, the random acylation of amino groups in wild-type RNase A with folic acid is shown to decrease its catalytic activity dramatically, presumably because of the alteration to a key active-site residue, Lys41. To effect site-specific coupling, N(δ)-bromoacetyl-N(α)-pteroyl-l-ornithine, which is a folate analogue with an electrophilic bromoacetamido group, was synthesized and used to S-alkylate Cys88 of the G88C variant of RNase A. The pendant folate moiety does not decrease enzymatic activity, enables RI-evasion, and endows toxicity for cancer cells that over-produce the folate receptor. These data reveal a propitious means for targeting proteins and other molecules to cancer cells.
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Ácido Fólico/química , Hormonas Placentarias/química , Acilación , Animales , Catálisis , Dominio Catalítico , Bovinos , Concentración 50 Inhibidora , Espectrometría de MasasRESUMEN
The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT. Tumor heterogeneity for secondary resistant KIT mutations within the same patient adds further complexity to GIST treatment. Several other mechanisms converge and reactivate the MAPK pathway upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and impairing cytotoxicity. To address the multiple potential pathways of drug resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the FDA for the treatment of adult patients with advanced GIST who have received previous treatment with 3 or more kinase inhibitors, including imatinib. Here we show that ripretinib treatment in combination with MEK inhibitors is effective at inducing and enhancing the apoptotic response and preventing growth of resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, even after long-term removal of drugs. The effect was also observed in systemic mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the driver mutation. Our results show that the combination of KIT and MEK inhibition has the potential to induce cytocidal responses in GIST and SM cells.
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Apoptosis/efectos de los fármacos , Tumores del Estroma Gastrointestinal/metabolismo , Mastocitosis Sistémica/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Urea/análogos & derivados , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/etiología , Tumores del Estroma Gastrointestinal/patología , Humanos , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/etiología , Ratones , Urea/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.
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Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Animales , Proliferación Celular , Estudios Cruzados , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Adulto JovenRESUMEN
Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
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Adenosina Trifosfato/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Células HeLa , Humanos , Cinética , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacología , Fosforilación , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Células CHO , Línea Celular , Línea Celular Tumoral , Cricetulus , Resistencia a Antineoplásicos/genética , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Células HCT116 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Mutación/efectos de los fármacos , Mutación/genéticaRESUMEN
The improper regulation of angiogenesis is implicit in a variety of diseases, including cancer. Angiogenin is unique among angiogenic factors in having ribonucleolytic activity. Inhibitors of this activity could serve as chemotherapeutics. The ribonucleolytic activity of angiogenin is toxic to the Origami strain of Escherichia coli. Herein, this cytotoxicity was used to identify inhibitors from a random nonapeptide library tethered to the C-terminus of human angiogenin. The selected sequences fell into three classes: (i) extremely hydrophobic, (ii) putative protease (ClpXP) substrates and (iii) slightly anionic. Two peptides corresponding to sequences in the last class were synthesized chemically and found to inhibit the ribonucleolytic activity of human angiogenin in vitro with micromolar values of Ki. Both peptides also inhibit bovine pancreatic ribonuclease, a homolog of angiogenin, though one exhibits selectivity for angiogenin. The affinity and selectivity of these peptides are comparable with the best known inhibitors of angiogenin. Moreover, the strategy used to identify them is general and could be applied to other cytotoxins.
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Péptidos/farmacología , Ingeniería de Proteínas/métodos , Ribonucleasa Pancreática/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Técnicas Genéticas , Humanos , Cinética , Modelos Biológicos , Péptido Hidrolasas/metabolismo , Biblioteca de Péptidos , Péptidos/química , Ribonucleasa Pancreática/química , Ribonucleasa Pancreática/genéticaRESUMEN
Homologous mammalian proteins were subjected to an exhaustive search for residues that are critical to their structure/function. Error-prone polymerase chain reactions were used to generate random mutations in the genes of bovine pancreatic ribonuclease (RNase A) and human angiogenin, and a genetic selection based on the intrinsic cytotoxicity of ribonucleolytic activity was used to isolate inactive variants. Twenty-three of the 124 residues in RNase A were found to be intolerant to substitution with at least one particular amino acid. Twenty-nine of the 123 residues in angiogenin were likewise intolerant. In both RNase A and angiogenin, only six residues appeared to be wholly intolerant to substitution: two histidine residues involved in general acid/base catalysis and four cysteine residues that form two disulfide bonds. With few exceptions, the remaining critical residues were buried in the hydrophobic core of the proteins. Most of these residues were found to tolerate only conservative substitutions. The importance of a particular residue as revealed by this genetic selection correlated with its sequence conservation, though several non-conserved residues were found to be critical for protein structure/function. Despite voluminous research on RNase A, the importance of many residues identified herein was unknown, and those can now serve as targets for future work. Moreover, a comparison of the critical residues in RNase A and human angiogenin, which share only 35% amino acid sequence identity, provides a unique perspective on the molecular evolution of the RNase A superfamily, as well as an impetus for applying this methodology to other ribonucleases.
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Ribonucleasa Pancreática/química , Ribonucleasa Pancreática/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Bovinos , Secuencia Conservada , Evolución Molecular , Humanos , Técnicas In Vitro , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Biblioteca de Péptidos , Conformación Proteica , Ribonucleasa Pancreática/antagonistas & inhibidores , Selección Genética , Homología de Secuencia de AminoácidoRESUMEN
Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486-501. ©2017 AACR.
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Neoplasias de la Mama/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazoles/farmacología , Piridinas/farmacología , Quinolinas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Angiopoyetinas/antagonistas & inhibidores , Angiopoyetinas/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Receptor TIE-2/genética , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy. METHODS: We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone. RESULTS: In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone. CONCLUSIONS: Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma.
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Neoplasias Encefálicas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Bevacizumab/farmacología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Femenino , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Neovascularización Patológica/tratamiento farmacológico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Receptor TIE-2/antagonistas & inhibidores , Células Tumorales Cultivadas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
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Aminopiridinas/farmacología , Anilidas/farmacología , Resistencia a Antineoplásicos , Neovascularización Patológica , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Receptor TIE-2/antagonistas & inhibidores , Microambiente Tumoral , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminopiridinas/química , Anilidas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bevacizumab/química , Bevacizumab/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Diseño de Fármacos , Quimioterapia Combinada , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Concentración 50 Inhibidora , Melanoma Experimental , Ratones , Modelos Moleculares , Conformación Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor TIE-2/metabolismo , Proteínas Recombinantes , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
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Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Pirimidinas/química , Pirimidinas/farmacología , Proteínas ras/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral/efectos de los fármacos , Técnicas de Química Sintética , Perros , Femenino , Semivida , Humanos , Masculino , Ratones Desnudos , Terapia Molecular Dirigida , Mutación , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacocinética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas ras/genéticaRESUMEN
LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.
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Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Isoformas de Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Pirimidinas/farmacología , Proteínas ras/genética , Línea Celular Tumoral , Dimerización , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Mutación/efectos de los fármacos , Mutación/genética , Neoplasias/genética , Fosforilación/efectos de los fármacos , Fosforilación/genética , Isoformas de Proteínas/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-raf/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Molecular probes are useful for both studying and controlling the functions of enzymes and other proteins. The most useful probes have high affinity for their target, along with small size and resistance to degradation. Here, we report on new surrogates for nucleic acids that fulfill these criteria. Isosteres in which phosphoryl [R-O-P(O(2)(-))-O-R'] groups are replaced with N-acylsulfonamidyl [R-C(O)-N(-)-S(O(2))-R'] or sulfonimidyl [R-S(O(2))-N(-)-S(O(2))-R'] groups increase the number of nonbridging oxygens from two (phosphoryl) to three (N-acylsulfonamidyl) or four (sulfonimidyl). Six such isosteres were found to be more potent inhibitors of catalysis by bovine pancreatic RNase A than are parent compounds containing phosphoryl groups. The atomic structures of two RNase A·N-acylsulfonamide complexes were determined at high resolution by X-ray crystallography. The N-acylsulfonamidyl groups were observed to form more hydrogen bonds with active site residues than did the phosphoryl groups in analogous complexes. These data encourage the further development and use of N-acylsulfonamides and sulfonimides as antagonists of nucleic acid-binding proteins.
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Inhibidores Enzimáticos/química , Nucleósidos/química , Ribonucleasa Pancreática/química , Animales , Sitios de Unión , Catálisis , Bovinos , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Enlace de Hidrógeno , Modelos Moleculares , Ribonucleasa Pancreática/antagonistas & inhibidores , Ribonucleasa Pancreática/metabolismoRESUMEN
Acquired point mutations within the BCR-ABL kinase domain represent a common mechanism of resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABL(T315I) mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCR-ABL(T315I) and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABL(T315I) enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC(50): 19 nmol/L), BCR-ABL(T315I) (IC(50): 63 nmol/L), and most kinase domain mutants. Ex vivo exposure of CML cells from patients harboring BCR-ABL or BCR-ABL(T315I) to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select P-loop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABL(E255V / T315I) as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML.