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1.
Cancer Res ; 84(6): 872-886, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38486486

RESUMO

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB. SIGNIFICANCE: Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.


Assuntos
Benzobromarona/análogos & derivados , Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Animais , Camundongos , Humanos , Criança , Proteínas Hedgehog , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Neoplasias Cerebelares/tratamento farmacológico
2.
Bioorg Med Chem Lett ; 68: 128718, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35378251

RESUMO

The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Mutação , Fenóis , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
3.
Nat Cancer ; 3(4): 402-417, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35422503

RESUMO

Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Trifosfato de Adenosina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia
4.
Free Radic Biol Med ; 178: 360-368, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34843917

RESUMO

Late-stage dry age-related macular degeneration (AMD) or geographic atrophy (GA) is an irreversible blinding condition characterized by degeneration of retinal pigment epithelium (RPE) and the associated photoreceptors. Clinical and genetic evidence supports a role for dysfunctional lipid processing and accumulation of harmful oxidized lipids in the pathogenesis of GA. Using an oxidized low-density lipoprotein (ox-LDL)-induced RPE death assay, we screened and identified sterically-hindered phenol compounds with potent protective activities for RPE. The phenol-containing PPARγ agonist, troglitazone, protected against ox-LDL-induced RPE cell death, whereas other more potent PPARγ agonists did not protect RPE cells. Knockdown of PPARγ did not affect the protective activity of troglitazone in RPE, confirming the protective function is not due to the thiazolidine (TZD) group of troglitazone. Prototypical hindered phenol trolox and its analogs potently protected against ox-LDL-induced RPE cell death whereas potent antioxidants without the phenol group failed to protect RPE. Hindered phenols preserved lysosomal integrity against ox-LDL-induced damage and FITC-labeled trolox was localized to the lysosomes in RPE cells. Analogs of trolox inhibited reactive oxygen species (ROS) formation induced by ox-LDL uptake in a dose-dependent fashion and were effective at sub-micromolar concentrations. Treatment with trolox analog 2,2,5,7,8-pentamethyl-6-chromanol (PMC) significantly induced the expression of the lysosomal protein NPC-1 and reduced intracellular cholesterol level upon ox-LDL uptake. Our data indicate that the lysosomal-localized hindered phenols are uniquely potent in protecting the RPE against the toxic effects of ox-LDL, and may represent a novel pharmacotherapy to preserve the vision in patients with GA.


Assuntos
Lipoproteínas LDL , Epitélio Pigmentado da Retina , Células Epiteliais , Humanos , Fenóis , Pigmentos da Retina
5.
Clin Cancer Res ; 26(24): 6535-6549, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32988967

RESUMO

PURPOSE: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2-selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL-mediated thrombocytopenia. EXPERIMENTAL DESIGN: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. RESULTS: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-xL-dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2-selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL-dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. CONCLUSIONS: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonas/farmacologia , Trombocitopenia/tratamento farmacológico , Proteína bcl-X/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Apoptose , Benzamidas/uso terapêutico , Proliferação de Células , Feminino , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Piperidinas/uso terapêutico , Sulfonas/uso terapêutico , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Bioorg Med Chem Lett ; 30(19): 127456, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739400

RESUMO

The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.


Assuntos
Benzodiazepinonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Benzodiazepinonas/síntese química , Benzodiazepinonas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Relação Estrutura-Atividade
8.
Cell Chem Biol ; 27(1): 19-31.e6, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31883964

RESUMO

KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRASG12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRASG12Cin vitro, induced CRBN/KRASG12C dimerization, and degraded GFP-KRASG12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRASG12C.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
9.
ACS Med Chem Lett ; 10(11): 1549-1553, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31749909

RESUMO

Allosteric kinase inhibitors represent a promising new therapeutic strategy for targeting kinases harboring oncogenic driver mutations in cancers. Here, we report the discovery, optimization, and structural characterization of allosteric mutant-selective EGFR inhibitors comprising a 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor (3) of the EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S) mutants with an IC50 of ∼10 nM and high selectivity, as assessed by kinome profiling. Further efforts to develop allosteric dibenzodiazepinone inhibitors may serve as the basis for new therapeutic options for targeting drug-resistant EGFR mutations.

10.
Cancer Discov ; 9(7): 926-943, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31092401

RESUMO

Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth, and an increased efficacy in vitro and in vivo compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant-selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with EGFR-mutant lung cancer. SIGNIFICANCE: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib.This article is highlighted in the In This Issue feature, p. 813.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Benzenoacetamidas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Regulação Alostérica , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Med Chem ; 61(12): 5235-5244, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29856615

RESUMO

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).


Assuntos
Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Humanos , Janus Quinase 1/química , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cell Chem Biol ; 24(8): 1005-1016.e3, 2017 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-28781124

RESUMO

Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.


Assuntos
Acrilamidas/química , Quinazolinas/química , Proteínas ras/metabolismo , Células A549 , Acrilamidas/metabolismo , Acrilamidas/farmacologia , Amidas/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Células HCT116 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Fosforilação/efeitos dos fármacos , Estrutura Terciária de Proteína , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Proteínas ras/antagonistas & inibidores , Proteínas ras/genética
13.
Bioorg Med Chem Lett ; 24(14): 3026-33, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24881567

RESUMO

Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.


Assuntos
Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteína bcl-X/antagonistas & inibidores , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteína bcl-X/metabolismo
14.
Bioorg Med Chem Lett ; 23(16): 4591-6, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23842474

RESUMO

The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.


Assuntos
Aminoquinolinas/síntese química , Aminoquinolinas/toxicidade , Compostos de Anilina/síntese química , Compostos de Anilina/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/toxicidade , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cobaias , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Ratos
15.
J Med Chem ; 55(11): 5130-42, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22551018

RESUMO

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKß, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.


Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Tiofenos/síntese química , Ureia/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Dano ao DNA , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desenho de Fármacos , Sinergismo Farmacológico , Ensaios de Triagem em Larga Escala , Irinotecano , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia , Ureia/síntese química , Ureia/química , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
18.
Bioorg Med Chem Lett ; 19(3): 701-5, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19114305

RESUMO

The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.


Assuntos
Química Farmacêutica/métodos , Neoplasias/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos
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