RESUMEN
Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.
RESUMEN
FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.
Asunto(s)
Antineoplásicos/uso terapéutico , Drogas en Investigación/uso terapéutico , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Drogas en Investigación/administración & dosificación , Drogas en Investigación/metabolismo , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Femenino , Xenoinjertos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Ratas , Ratas Desnudas , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.
Asunto(s)
Adenosina Trifosfato/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Anciano , Línea Celular Tumoral , Colangiocarcinoma/diagnóstico , ADN Tumoral Circulante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/química , Pirimidinas/farmacología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/química , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Tomografía Computarizada por Rayos XRESUMEN
A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.
Asunto(s)
Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridinas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Células HeLa , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa Tipo Polo 1RESUMEN
Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.
Asunto(s)
Dipéptidos/síntesis química , Piperidinas/síntesis química , Receptor Muscarínico M3/antagonistas & inhibidores , Compuestos de Tritilo/síntesis química , Secuencia de Aminoácidos , Animales , Células CHO , Cricetinae , Cricetulus , Dipéptidos/química , Dipéptidos/farmacología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Piperidinas/química , Piperidinas/farmacología , Receptor Muscarínico M3/química , Estereoisomerismo , Relación Estructura-Actividad , Compuestos de Tritilo/química , Compuestos de Tritilo/farmacologíaRESUMEN
5-Pyrimidinyl-2-aminothiazole 1 was identified as an inhibitor of cyclin-dependent kinases (CDKs) by a screening of the Merck sample repository. The introduction of a methyl group at the C-5 or C-6 position on the pyrimidine ring, directed toward the gate keeper residue of CDK4 (Phe93), led to significant enhancement of selectivity for CDK4 over other CDKs. Compound 3 exhibited more than 300-fold selectivity for CDK4 over CDK1, 2, 5, 7, and 9. Subsequent improvements in aqueous solubility afforded compound 4, which is available for further in vivo studies and this compound inhibited pRb phosphorylation and BrdU incorporation in tumor models.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Tiazoles/farmacología , Bromodesoxiuridina/antagonistas & inhibidores , Bromodesoxiuridina/metabolismo , Proteína Quinasa CDC2/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Humanos , Fosforilación , Proteína de Retinoblastoma/antagonistas & inhibidores , Proteína de Retinoblastoma/metabolismo , Células Tumorales Cultivadas , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library was designed based on 3D-pharmacophore similarity to known actives. A novel D-proline amide class was identified in this library and was found to possess potent ORL1 antagonistic activity.