RESUMEN
RET rearrangement is a recently identified oncogenic mutation in lung adenocarcinoma (LADC) that accounts for approximately 2% of all NSCLCs. More than six fusion partners have been identified in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1 and ERC1. Many RET inhibitors have been reported and some have progressed to the clinic. Similar to most kinase inhibitors, patients often respond to current RET inhibitors but relapse can occur due to the emergence of mutant RET kinases, such as RET (S904F) and (V804L/M), which are resistant to inhibition. Our group previously reported that the benzamide aminonaphthyridine HSN356, a multikinase inhibitor, also inhibited RET. In this study, we prepared various nicotinamide analogs of HSN356 and investigated RET inhibition to uncover the salient moieties on HSN356 that are important for kinase inhibition and to also evaluate if HSN356 and analogs thereof could inhibit mutant RET kinases, such as RET (S904F) and (V804L/M). Compound 3 (HSN608), the nicotinamide analog of HSN356, inhibits RET and mutant forms better than reported RET inhibitors such as Alectinib, Sorafenib, Vandetanib and Apatinib, and comparable to BLU667. HSN608 inhibited the growth of CCDC6-RET driven LC-2/ad cell line with IC50 of ~3â¯nM. Under similar conditions, BLU667 and vandetanib (two drugs being evaluated against RET-driven cancers in the clinic) inhibited the growth of LC-2/ad with IC50 values of ~10 and 328â¯nM respectively.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Naftiridinas/farmacología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/síntesis química , Benzamidas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Estructura Molecular , Mutación , Naftiridinas/síntesis química , Naftiridinas/química , Niacinamida/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-ret/genética , Relación Estructura-ActividadRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to <10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD). Inhibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but patients often relapse due to secondary mutations in the FLT3 TKD, like D835Y and F691â¯L mutations. METHODS: Alkynyl aminoisoquinoline and naphthyridine compounds were synthesized via Sonogashira coupling. The compounds were evaluated for their in vitro and in vivo effects on leukemia growth. FINDINGS: The compounds inhibited FLT3 kinase activity at low nanomolar concentrations. The lead compound, HSN431, also inhibited Src kinase activity. The compounds potently inhibited the viability of MV4-11 and MOLM-14 AML cells with IC50 values <1â¯nM. Furthermore, the viability of drug-resistant AML cells harboring the D835Y and F691â¯L mutations were potently inhibited. In vivo efficacy studies in mice demonstrated that the compounds could drastically reduce AML proliferation in mice. INTERPRETATION: Compounds that inhibit FLT3 and downstream targets like Src (for example HSN431) are good leads for development as anti-AML agents. FUND: Purdue University, Purdue Institute for Drug Discovery (PIDD), Purdue University Center for Cancer Research, Elks Foundation and NIH P30 CA023168.
Asunto(s)
Antineoplásicos/farmacología , Isoquinolinas/farmacología , Naftiridinas/farmacología , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Isoquinolinas/química , Leucemia Mieloide Aguda , Ratones , Estructura Molecular , Mutación , Naftiridinas/química , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
Cyclin-dependent kinases have emerged as important targets for cancer therapy. HSD992, containing a novel scaffold based on the tetrahydro-3H-pyrazolo[4,3-a]phenanthridine core, inhibits CDK2/3 but not other CDKs and also potently inhibits several cancer cell lines.
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Fenantridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Dominio Catalítico , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/química , Quinasa 3 Dependiente de Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Fenantridinas/síntesis química , Fenantridinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Estaurosporina/farmacologíaRESUMEN
The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline- or naphthyridine-based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1-driven CML cell lines, K652 and KCL22 as well as the drug-resistant cell line, KCL22-IR, which harbors the secondary mutated ABL1(T315I) kinase.
Asunto(s)
Alquinos/farmacología , Antineoplásicos/farmacología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Alquinos/síntesis química , Alquinos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Mesilato de Imatinib/farmacología , Imidazoles/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/química , Isoquinolinas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ratones , Simulación del Acoplamiento Molecular , Naftiridinas/síntesis química , Naftiridinas/química , Naftiridinas/farmacología , Niacinamida/síntesis química , Niacinamida/química , Mutación Puntual , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/química , Proteínas Proto-Oncogénicas c-abl/genética , Piridazinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacologíaRESUMEN
AIM: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven resistance mechanisms. The development of FLT3 inhibitors that also target other downstream oncogenic kinases may combat the resistance mechanism. RESULTS: 4-substituted aminoisoquinoline benzamides potently inhibit Src-family kinases and FLT3, including secondary mutations, such as FLT3D835. Modifications of aminoisoquinoline benzamide to aminoquinoline or aminoquinazoline abrogated FLT3 and Src-family kinase binding. CONCLUSION: The lead aminoisoquinolines potently inhibited FLT3-driven AML cell lines, MV4-11 and MOLM-14. These aminoisoquinoline benzamides represent new kinase scaffolds with high potential to be translated into anticancer agents.