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1.
Cancer Res ; 83(19): 3170-3173, 2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37779429

RESUMEN

Following three decades of systematic primary empirical screening against mice bearing two transplantable murine leukemias, the NCI took the bold step of switching to a radically different approach-initial screening of 10,000 diverse compounds/year against a panel of 60 human tumor cell lines in vitro. The establishment of the "NCI-60" screen was announced in the landmark Cancer Research article by Alley and colleagues, published in 1988, which exemplified the technological basis for the new microculture screen, operating at unprecedented scale. The underlying concept was that NCI-60 might expedite the discovery of innovative cancer drugs, especially those with predicted activity against particular solid cancers-not then possible. We discuss how NCI-60 provided a major technological advance and delivered a successful legacy for cancer research and development. While not immediately cracking the thorny problem of model-to-human tumor type prediction, NCI-60 nevertheless provided the conceptual and methodologic foundation for subsequent, much larger-scale human cancer cell panel screens with detailed molecular annotation and sophisticated informatics. Now used in modern molecular target-based drug discovery, these panels help enable the implementation of contemporary biomarker-led precision oncology. See related article by Alley and colleagues, Cancer Res 1988;48:589-601.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Animales , Ratones , Evaluación Preclínica de Medicamentos , Estudios de Factibilidad , Detección Precoz del Cáncer , Medicina de Precisión , Antineoplásicos/farmacología , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/genética
2.
Cancer Discov ; 13(10): 2150-2165, 2023 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-37712569

RESUMEN

Small-molecule chemical "probes" complement the use of molecular biology techniques to explore, validate, and generate hypotheses on the function of proteins in diseases such as cancer. Unfortunately, the poor selection and use of small-molecule reagents can lead to incorrect conclusions. Here, we illustrate examples of poor chemical tools and suggest best practices for the selection, validation, and use of high-quality chemical probes in cancer research. We also note the complexity associated with tools for novel drug modalities, exemplified by protein degraders, and provide advice and resources to facilitate the independent identification of appropriate small-molecule probes by researchers. SIGNIFICANCE: Validation of biological targets and pathways will be aided by a shared understanding of the criteria of potency, selectivity, and target engagement associated with small-molecule reagents ("chemical probes") that enable that work. Interdisciplinary collaboration between cancer biologists, medicinal chemists, and chemical biologists and the awareness of available resources will reduce misleading data generation and interpretation, strengthen data robustness, and improve productivity in academic and industrial research.


Asunto(s)
Neoplasias , Investigación , Humanos , Proteínas , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
3.
J Med Chem ; 66(8): 5907-5936, 2023 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-37017629

RESUMEN

CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early compound optimization; central ring halogen substitution was demonstrated by matched molecular pair analysis to be an effective strategy to mitigate this liability. Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Factores de Transcripción/metabolismo , Neoplasias Ováricas/patología , Línea Celular Tumoral , Antineoplásicos/farmacología
4.
Nucleic Acids Res ; 51(D1): D1212-D1219, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36624665

RESUMEN

canSAR (https://cansar.ai) is the largest public cancer drug discovery and translational research knowledgebase. Now hosted in its new home at MD Anderson Cancer Center, canSAR integrates billions of experimental measurements from across molecular profiling, pharmacology, chemistry, structural and systems biology. Moreover, canSAR applies a unique suite of machine learning algorithms designed to inform drug discovery. Here, we describe the latest updates to the knowledgebase, including a focus on significant novel data. These include canSAR's ligandability assessment of AlphaFold; mapping of fragment-based screening data; and new chemical bioactivity data for novel targets. We also describe enhancements to the data and interface.


Asunto(s)
Antineoplásicos , Descubrimiento de Drogas , Bases del Conocimiento , Investigación Biomédica Traslacional , Humanos , Algoritmos , Neoplasias/tratamiento farmacológico , Neoplasias/genética
5.
Mol Cell Proteomics ; 22(2): 100485, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36549590

RESUMEN

The molecular chaperone heat shock protein 90 (HSP90) works in concert with co-chaperones to stabilize its client proteins, which include multiple drivers of oncogenesis and malignant progression. Pharmacologic inhibitors of HSP90 have been observed to exert a wide range of effects on the proteome, including depletion of client proteins, induction of heat shock proteins, dissociation of co-chaperones from HSP90, disruption of client protein signaling networks, and recruitment of the protein ubiquitylation and degradation machinery-suggesting widespread remodeling of cellular protein complexes. However, proteomics studies to date have focused on inhibitor-induced changes in total protein levels, often overlooking protein complex alterations. Here, we use size-exclusion chromatography in combination with mass spectrometry (SEC-MS) to characterize the early changes in native protein complexes following treatment with the HSP90 inhibitor tanespimycin (17-AAG) for 8 h in the HT29 colon adenocarcinoma cell line. After confirming the signature cellular response to HSP90 inhibition (e.g., induction of heat shock proteins, decreased total levels of client proteins), we were surprised to find only modest perturbations to the global distribution of protein elution profiles in inhibitor-treated HT29 cells at this relatively early time-point. Similarly, co-chaperones that co-eluted with HSP90 displayed no clear difference between control and treated conditions. However, two distinct analysis strategies identified multiple inhibitor-induced changes, including known and unknown components of the HSP90-dependent proteome. We validate two of these-the actin-binding protein Anillin and the mitochondrial isocitrate dehydrogenase 3 complex-as novel HSP90 inhibitor-modulated proteins. We present this dataset as a resource for the HSP90, proteostasis, and cancer communities (https://www.bioinformatics.babraham.ac.uk/shiny/HSP90/SEC-MS/), laying the groundwork for future mechanistic and therapeutic studies related to HSP90 pharmacology. Data are available via ProteomeXchange with identifier PXD033459.


Asunto(s)
Adenocarcinoma , Antineoplásicos , Neoplasias del Colon , Humanos , Proteoma/metabolismo , Adenocarcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico , Chaperonas Moleculares , Antineoplásicos/farmacología , Espectrometría de Masas , Cromatografía en Gel
6.
Drug Discov Today ; 27(4): 946-950, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34954130

RESUMEN

New discoveries and technologies are driving major advances in our understanding of cancer and underpinning a new era of precision medicine and immunotherapy. However, advances in treatment have been uneven: whereas survival rates for some common cancers are improving rapidly, for others there has been much less progress. In addition, healthcare systems are finding it difficult to provide access to expensive new treatments. There is an urgent need for imaginative policy solutions to incentivise the creation of novel therapies that address the full range of cancer-causing mechanisms. We have worked with organisations across the medical research community to develop consensus statements on how to enhance access to innovative cancer drugs. Here, we present our reflections on these statements.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapéutico , Humanos , Factores Inmunológicos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Medicina de Precisión
7.
Cancer Res ; 81(24): 6207-6218, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34753775

RESUMEN

It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow-derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth in vitro, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody-drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Biomarcadores de Tumor/metabolismo , Camptotecina/análogos & derivados , Neurregulina-1/metabolismo , Organoides/patología , Neoplasias de la Próstata/patología , Receptor ErbB-3/antagonistas & inhibidores , Animales , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Camptotecina/farmacología , Proliferación Celular , Estudios de Seguimiento , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Neurregulina-1/genética , Organoides/efectos de los fármacos , Organoides/metabolismo , Pronóstico , Estudios Prospectivos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Nat Commun ; 12(1): 6738, 2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-34795259

RESUMEN

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Daño del ADN , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Oxaliplatino/administración & dosificación , Neoplasias Pancreáticas/genética
9.
Cell Chem Biol ; 28(10): 1433-1445.e3, 2021 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-34077750

RESUMEN

Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.


Asunto(s)
Descubrimiento de Drogas , Evolución Molecular , Proteínas HSP90 de Choque Térmico/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Sitios de Unión , Receptor con Dominio Discoidina 1/antagonistas & inhibidores , Receptor con Dominio Discoidina 1/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Isoxazoles/química , Isoxazoles/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/metabolismo , Resorcinoles/química , Resorcinoles/metabolismo , Triazoles/química , Triazoles/metabolismo
10.
Trends Pharmacol Sci ; 42(5): 313-315, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33771354

RESUMEN

Casein kinase 2 (CK2) is highly expressed in cancer and has been considered a potential therapeutic target. Wells and colleagues developed and characterized the new CK2 inhibitor SGC-CK2-1. Unexpectedly, this potent and highly selective chemical probe does not show broad antiproliferative activity in cancer cells.


Asunto(s)
Quinasa de la Caseína II , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas
11.
Nat Rev Clin Oncol ; 18(7): 454-467, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33762744

RESUMEN

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based 'liquid biopsy' approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials.


Asunto(s)
Antineoplásicos/uso terapéutico , Desarrollo de Medicamentos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Algoritmos , Antineoplásicos/aislamiento & purificación , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/sangre , Auditoría Clínica/métodos , Auditoría Clínica/organización & administración , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/organización & administración , Humanos , Biopsia Líquida , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/patología , Pronóstico
12.
Cell Rep Med ; 2(1): 100188, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33521702

RESUMEN

Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition, leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape and autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition, which globally downregulates transcription, leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.


Asunto(s)
Biomarcadores de Tumor/genética , Cordoma/genética , Quinasas Ciclina-Dependientes/genética , Proteínas Fetales/genética , Proteínas de Neoplasias/genética , Neoplasias de la Columna Vertebral/genética , Proteínas de Dominio T Box/genética , Secuencia de Bases , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Cordoma/metabolismo , Cordoma/patología , Quinasas Ciclina-Dependientes/metabolismo , Proteínas Fetales/metabolismo , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Células HEK293 , Histonas/genética , Histonas/metabolismo , Humanos , Queratina-18/genética , Queratina-18/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas de Neoplasias/metabolismo , Proteolisis , Transducción de Señal , Neoplasias de la Columna Vertebral/metabolismo , Neoplasias de la Columna Vertebral/patología , Proteínas de Dominio T Box/metabolismo
13.
Nucleic Acids Res ; 49(D1): D1074-D1082, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33219674

RESUMEN

canSAR (http://cansar.icr.ac.uk) is the largest, public, freely available, integrative translational research and drug discovery knowledgebase for oncology. canSAR integrates vast multidisciplinary data from across genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and more. It also provides unique data, curation and annotation and crucially, AI-informed target assessment for drug discovery. canSAR is widely used internationally by academia and industry. Here we describe significant developments and enhancements to the data, web interface and infrastructure of canSAR in the form of the new implementation of the system: canSARblack. We demonstrate new functionality in aiding translation hypothesis generation and experimental design, and show how canSAR can be adapted and utilised outside oncology.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Descubrimiento de Drogas/métodos , Bases del Conocimiento , Neoplasias/genética , Investigación Biomédica Traslacional/métodos , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Minería de Datos/métodos , Genómica/métodos , Humanos , Internet , Oncología Médica/métodos , Estructura Molecular , Neoplasias/metabolismo , Proteómica/métodos , Interfaz Usuario-Computador
14.
J Clin Invest ; 130(11): 5875-5892, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33016930

RESUMEN

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.


Asunto(s)
Adenosina/análogos & derivados , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Proteína Proto-Oncogénica N-Myc/biosíntesis , Neuroblastoma/tratamiento farmacológico , Temozolomida/farmacología , Adenosina/farmacología , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 9 Dependiente de la Ciclina/metabolismo , Elementos de Facilitación Genéticos , Humanos , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , Factor B de Elongación Transcripcional Positiva/genética , Factor B de Elongación Transcripcional Positiva/metabolismo , Transcripción Genética/efectos de los fármacos
15.
Sci Rep ; 10(1): 16000, 2020 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-32994435

RESUMEN

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic 'client' proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native 'carboxylate clamp' interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H-15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.


Asunto(s)
Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Dominio Catalítico , Simulación por Computador , Humanos , Ligandos , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Unión Proteica , Conformación Proteica , Dominios Proteicos , Bibliotecas de Moléculas Pequeñas/química
16.
Adv Exp Med Biol ; 1243: C1-C2, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32965646

RESUMEN

The original version of the book was revised: Chapter 11 is now available open access under a CC BY 4.0 license and the copyright holder has been changed to 'The Author(s)'.

17.
PLoS One ; 15(7): e0234103, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32645016

RESUMEN

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).


Asunto(s)
Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Animales , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 9 Dependiente de la Ciclina/efectos de los fármacos , Quinasa 9 Dependiente de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Humanos , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Sulfonamidas/farmacología
18.
Adv Exp Med Biol ; 1243: 163-179, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32297218

RESUMEN

This personal perspective focuses on small-molecule inhibitors of proteostasis networks in cancer-specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. Emphasis is on progress made and lessons learned and a future outlook is provided. Highly potent, selective HSP90 inhibitors have proved invaluable in exploring the role of this molecular chaperone family in biology and disease pathology. Clinical activity was observed, especially in non small cell lung cancer and HER2 positive breast cancer. Optimal use of HSP90 inhibitors in oncology will likely require development of creative combination strategies. HSP70 family members have proved technically harder to drug. However, recent progress has been made towards useful chemical tool compounds and these may signpost future clinical drug candidates. The HSF1 stress pathway is strongly validated as a target for cancer therapy. HSF1 itself is a ligandless transcription factor that is extremely challenging to drug directly. HSF1 pathway inhibitors have been identified mostly by phenotypic screening, including a series of bisamides from which a clinical candidate has been identified for treatment of ovarian cancer, multiple myeloma and potentially other cancers.


Asunto(s)
Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Factores de Transcripción del Choque Térmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Humanos , Neoplasias/genética , Proteostasis/efectos de los fármacos
19.
Cancer Res ; 80(8): 1735-1747, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32161100

RESUMEN

Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell-cycle progression, DNA damage repair, and DNA replication. Small-molecule CHK1 inhibitors sensitize cancer cells to genotoxic agents and have shown single-agent preclinical activity in cancers with high levels of replication stress. However, the underlying genetic determinants of CHK1 inhibitor sensitivity remain unclear. We used the developmental clinical drug SRA737 in an unbiased large-scale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified subunits of the B-family of DNA polymerases (POLA1, POLE, and POLE2) whose silencing sensitized the human A549 non-small cell lung cancer (NSCLC) and SW620 colorectal cancer cell lines to SRA737. B-family polymerases were validated using multiple siRNAs in a panel of NSCLC and colorectal cancer cell lines. Replication stress, DNA damage, and apoptosis were increased in human cancer cells following depletion of the B-family DNA polymerases combined with SRA737 treatment. Moreover, pharmacologic blockade of B-family DNA polymerases using aphidicolin or CD437 combined with CHK1 inhibitors led to synergistic inhibition of cancer cell proliferation. Furthermore, low levels of POLA1, POLE, and POLE2 protein expression in NSCLC and colorectal cancer cells correlated with single-agent CHK1 inhibitor sensitivity and may constitute biomarkers of this phenotype. These findings provide a potential basis for combining CHK1 and B-family polymerase inhibitors in cancer therapy. SIGNIFICANCE: These findings demonstrate how the therapeutic benefit of CHK1 inhibitors may potentially be enhanced and could have implications for patient selection and future development of new combination therapies.


Asunto(s)
Afidicolina/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Retinoides/farmacología , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Daño del ADN , ADN Polimerasa I/antagonistas & inhibidores , ADN Polimerasa I/genética , ADN Polimerasa I/metabolismo , ADN Polimerasa II/antagonistas & inhibidores , ADN Polimerasa II/genética , ADN Polimerasa II/metabolismo , ADN Polimerasa beta , Drogas en Investigación/farmacología , Inhibidores Enzimáticos/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Interferente Pequeño/análisis , ARN Interferente Pequeño/genética
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