RESUMO
The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1-6. Despite advances in treatment with immune checkpoint inhibitors7-10, there is an unmet need in the treatment of MSI cancers11-14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.
Assuntos
Antineoplásicos , Descoberta de Drogas , Inibidores Enzimáticos , Instabilidade de Microssatélites , Neoplasias , Mutações Sintéticas Letais , Helicase da Síndrome de Werner , Animais , Feminino , Humanos , Camundongos , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Dano ao DNA/efeitos dos fármacos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Domínios Proteicos , Reprodutibilidade dos Testes , Supressão Genética , Mutações Sintéticas Letais/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Helicase da Síndrome de Werner/antagonistas & inibidores , Helicase da Síndrome de Werner/genética , Helicase da Síndrome de Werner/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.
Assuntos
Neoplasias , Fatores de Transcrição , Animais , Camundongos , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
Inhibition of the YAP-TEAD protein-protein interaction is an attractive therapeutic concept under intense investigation with the objective to treat cancers associated with a dysregulation of the Hippo pathway. However, owing to the very extended surface of interaction of the two proteins, the identification of small drug-like molecules able to efficiently prevent YAP from binding to TEAD by direct competition has been elusive so far. We disclose here the discovery of the first class of small molecules potently inhibiting the YAP-TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD. These inhibitors, providing a path forward to pharmacological intervention in the Hippo pathway, evolved from a weakly active virtual screening hit advanced to high potency by structure-based design.
Assuntos
Neoplasias , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal/química , Humanos , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
Assuntos
Indóis/química , Receptores de Grelina/agonistas , Animais , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Hormônio do Crescimento Humano/agonistas , Humanos , Indóis/farmacologia , Ratos , Receptores de Grelina/fisiologia , EstereoisomerismoRESUMO
UNLABELLED: Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of ß-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity. SIGNIFICANCE: The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Linhagem Celular Tumoral , Amplificação de Genes/efeitos dos fármacos , Células HEK293 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Camundongos , Modelos Moleculares , Neoplasias/genética , Neoplasias/patologia , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.
Assuntos
Antineoplásicos/síntese química , Compostos de Fenilureia/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Relação Estrutura-Atividade , Transplante Heterólogo , Neoplasias da Bexiga UrináriaRESUMO
A novel series of pyridone inhibitors has been identified through pharmacophore analysis, as potent antagonists of VLA-4.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Piridonas/síntese química , Piridonas/farmacologia , Sítios de Ligação , Desenho de Fármacos , Relação Estrutura-Atividade , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
A series of pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Piridonas/farmacologia , Administração Oral , Animais , Piridonas/administração & dosagem , Piridonas/farmacocinética , RatosRESUMO
A novel series of pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Quinase 3 da Glicogênio Sintase/química , Pirazóis/química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Pirazóis/síntese química , Piridazinas/síntese química , Modelos Moleculares , Pirazóis/química , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
A series of 6-heteroaryl-pyrazolo[3,4-b]pyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely related Cyclin Dependent Kinase-2 (CDK-2).
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Piridinas/síntese química , Animais , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Quinase 2 Dependente de Ciclina , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).