RESUMO
Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Nicotina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Conformação Molecular , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nicotina/síntese química , Nicotina/química , Nicotina/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sulfonas/síntese química , Quinase do Linfoma Anaplásico , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Cães , Humanos , Macaca fascicularis , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
Assuntos
Antimaláricos/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Fígado/parasitologia , Malária/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Eritrócitos/parasitologia , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Plasmodium/citologia , Plasmodium/crescimento & desenvolvimento , Plasmodium/fisiologia , Plasmodium berghei/citologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/fisiologia , Plasmodium falciparum/citologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/fisiologia , Plasmodium yoelii/citologia , Plasmodium yoelii/efeitos dos fármacos , Plasmodium yoelii/crescimento & desenvolvimento , Plasmodium yoelii/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Distribuição Aleatória , Bibliotecas de Moléculas Pequenas , Esporozoítos/efeitos dos fármacos , Esporozoítos/crescimento & desenvolvimentoRESUMO
Here we report the design and evaluation of a bifunctional, small molecule switch that induces a targeted immune response against tumors in vivo. A high affinity ligand for prostate specific membrane antigen (PSMA) was conjugated to a hapten that binds dinitrophenyl (DNP)-specific antibodies. When introduced into hu-PBL-NOD/SCID mice previously immunized with a KLH-DNP immunogen, this conjugate induced a targeted antibody-dependent cellular cytotoxicity (ADCC) response to PSMA-expressing tumor cells in a mouse xenograft model. The ability to create a small molecule inducible antibody response against self-antigens using endogenous non-autoreactive antibodies may provide advantages over the autologous immune response generated by conventional vaccines in certain therapeutic settings.