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Proc Natl Acad Sci U S A ; 121(7): e2315069121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315851


A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.

Doenças Transmissíveis , Descoberta de Drogas , Camundongos , Animais , Interações Medicamentosas , Modelos Animais de Doenças , Sistema Enzimático do Citocromo P-450/metabolismo , Aceleração
J Med Chem ; 63(10): 5367-5386, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32342688


In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-ß-d-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.

Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Hidantoínas/química , Hidantoínas/farmacologia , Oxirredutases do Álcool/metabolismo , Animais , Antituberculosos/metabolismo , Proteínas de Bactérias/metabolismo , Feminino , Células Hep G2 , Humanos , Hidantoínas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo
Nat Commun ; 7: 12581, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27581223


Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis ß-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related ß-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.

3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/genética , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Indazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/farmacologia , Tuberculose Pulmonar/tratamento farmacológico , Animais , Farmacorresistência Bacteriana/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único/genética , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/prevenção & controle