RESUMO
Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.
Assuntos
Descoberta de Drogas , Proteínas Proto-Oncogênicas p21(ras) , Animais , Cães , Humanos , Camundongos , Ratos , Administração Oral , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Relação Estrutura-AtividadeRESUMO
[reaction: see text] The nitrogen-based nucleophile generated from azodicarboxylate and triphenylphosphine displayed an excellent reactivity toward carbonyl compounds to generate a variety of different final products depending on the substituent pattern on the carbonyl carbon. From the structures of these adducts, a straightforward mechanistic interpretation for the formation of different products is provided.
Assuntos
Cetonas/química , Álcoois/química , Indicadores e Reagentes , Modelos Moleculares , Conformação MolecularRESUMO
Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
Assuntos
Amidas/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Baço/enzimologia , Amidas/síntese química , Amidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Mutagenicidade , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Baço/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617âPhe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.
Assuntos
Inibidores Enzimáticos/farmacologia , Janus Quinase 2/antagonistas & inibidores , Policitemia Vera/tratamento farmacológico , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Eritropoetina/metabolismo , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT5/metabolismoRESUMO
The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.
Assuntos
Carbolinas/síntese química , Indóis/síntese química , Janus Quinase 2/antagonistas & inibidores , Transtornos Mieloproliferativos/tratamento farmacológico , Piridinas/síntese química , Pirimidinas/síntese química , Administração Oral , Animais , Carbolinas/farmacocinética , Carbolinas/farmacologia , Cristalografia por Raios X , Cães , Haplorrinos , Hepatócitos/metabolismo , Indóis/farmacocinética , Indóis/farmacologia , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Fosforilação , Policitemia Vera/tratamento farmacológico , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Rhodium acetate-catalyzed hydroacylation between aldehydes and an activated form of N=N bond was achieved under mild conditions to provide efficient access to a variety of hydrazino imides. Good selectivity for the aldehydic C-H activation relative to the ene-type reaction was observed with aldehydes having unsaturation both at terminal and internal positions.