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1.
J Med Chem ; 67(6): 4541-4559, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38466661

RESUMO

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.


Assuntos
Neoplasias , Humanos , Entropia , Metionina Adenosiltransferase/metabolismo
2.
J Med Chem ; 66(13): 9147-9160, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37395055

RESUMO

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Neoplasias , Animais , Humanos , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias/tratamento farmacológico , Desenho de Fármacos , Glicina/uso terapêutico , Mutação , Neoplasias Pulmonares/tratamento farmacológico
3.
J Med Chem ; 65(9): 6940-6952, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35471939

RESUMO

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/farmacologia , Desenho de Fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinas/farmacologia , Relação Estrutura-Atividade
4.
J Med Chem ; 64(23): 17146-17183, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34807608

RESUMO

Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.


Assuntos
Inibidores Enzimáticos/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Regulação Alostérica , Animais , Domínio Catalítico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/química , Proteína Potenciadora do Homólogo 2 de Zeste/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Compostos Heterocíclicos/química , Humanos , Ligantes , Complexo Repressor Polycomb 2/química , Ratos , Relação Estrutura-Atividade
5.
J Med Chem ; 64(10): 6814-6826, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33900758

RESUMO

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Metionina Adenosiltransferase/antagonistas & inibidores , Sítio Alostérico , Animais , Proliferação de Células , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Técnicas de Inativação de Genes , Células HCT116 , Meia-Vida , Humanos , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinazolinas/química , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Ratos , S-Adenosilmetionina/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo
6.
Bioorg Med Chem Lett ; 39: 127904, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33684441

RESUMO

Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Purinas/farmacologia , Termodinâmica , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ligantes , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Complexo Repressor Polycomb 2/metabolismo , Purinas/síntese química , Purinas/química , Teoria Quântica , Relação Estrutura-Atividade
7.
J Med Chem ; 63(9): 4468-4483, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32023060

RESUMO

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Quinazolinas/uso terapêutico , Quinolonas/uso terapêutico , Regulação Alostérica , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Camundongos Nus , Conformação Molecular , Mutação , Piperazinas/síntese química , Piperazinas/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinolonas/síntese química , Quinolonas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 62(1): 247-265, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29672039

RESUMO

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.


Assuntos
Inibidores de Proteínas Quinases/química , Receptor trkA/antagonistas & inibidores , Regulação Alostérica , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Receptor trkA/metabolismo , Alinhamento de Sequência , Relação Estrutura-Atividade
9.
J Chem Inf Model ; 57(4): 897-909, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28319380

RESUMO

Optimization of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly because of its lack of accuracy and reproducibility as well as the long turnaround times required to obtain results. Herein we report on a collaborative study that compares tropomyosin receptor kinase A (TrkA) binding affinity predictions using two recently formulated fast computational approaches, namely, Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent (ESMACS) and Thermodynamic Integration with Enhanced Sampling (TIES), to experimentally derived TrkA binding affinities for a set of Pfizer pan-Trk compounds. ESMACS gives precise and reproducible results and is applicable to highly diverse sets of compounds. It also provides detailed chemical insight into the nature of ligand-protein binding. TIES can predict and thus optimize more subtle changes in binding affinities between compounds of similar structure. Individual binding affinities were calculated in a few hours, exhibiting good correlations with the experimental data of 0.79 and 0.88 from the ESMACS and TIES approaches, respectively. The speed, level of accuracy, and precision of the calculations are such that the affinity predictions can be used to rapidly explain the effects of compound modifications on TrkA binding affinity. The methods could therefore be used as tools to guide lead optimization efforts across multiple prospective structurally enabled programs in the drug discovery setting for a wide range of compounds and targets.


Assuntos
Desenho de Fármacos , Dor/tratamento farmacológico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Dor/enzimologia , Ligação Proteica , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/química , Termodinâmica
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