RESUMO
Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, piperidines, and azepanes bearing ester and diverse aryl substituents. A one-pot rhodium catalyzed N-H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m-haloamines (m=2-5) to rapidly assemble 4 -, 5 -, 6 -, and 7 -membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α-disubstituted amino acids and applied to fragment synthesis.
RESUMO
Spiro-3,2'-azetidine oxindoles combine two independently important pharmacophores in an understudied spirocyclic motif that is attractive for medicinal chemistry. Here, the enantioselective synthesis of these structures is achieved in up to 2:98 er through intramolecular C-C bond formation, involving activation of the substrate with a novel SF5-containing chiral cation phase-transfer (PT) catalyst. The products are readily elaborated/deprotected to afford medicinally relevant enantioenriched compounds. Control experiments suggest an interfacial PT mechanism, whereby catalytic asymmetric induction is achieved through the activation of the chloride leaving group.
RESUMO
The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes. This Perspective is our attempt to analyze reports of DEL screening with the purpose of providing a rigorous and useful account of the binding modes observed for DEL-derived ligands with a focus on binding mode novelty.
Assuntos
DNA , Bibliotecas de Moléculas Pequenas , Bibliotecas de Moléculas Pequenas/química , Ligantes , DNA/química , Descoberta de Drogas , Técnicas de Química CombinatóriaRESUMO
Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.
Assuntos
Desenho de Fármacos , Histona-Lisina N-Metiltransferase , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/química , Ligantes , Humanos , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Aprendizado de Máquina , Modelos Moleculares , Domínios ProteicosRESUMO
Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.
RESUMO
Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , c-Mer Tirosina Quinase/antagonistas & inibidores , Animais , Cristalografia por Raios X , Mineração de Dados , Descoberta de Drogas , Humanos , Modelos Moleculares , c-Mer Tirosina Quinase/química , c-Mer Tirosina Quinase/metabolismoRESUMO
Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Imidazóis/síntese química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/síntese química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , c-Mer Tirosina Quinase/metabolismo , Receptor Tirosina Quinase AxlRESUMO
Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.
Assuntos
Proteínas 14-3-3/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas 14-3-3/química , Desenho de Fármacos , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Conformação ProteicaRESUMO
Tuberculosis is a major health problem worldwide, with approximately 1.7 million people dying annually from the disease. The long current drug regimen, the emergence of drug resistant strains and HIV co-infection have resulted in a resurgence in research efforts to address the urgent need for new anti-tuberculosis drugs. A number of new potential anti-tuberculosis drug candidates with novel modes of action have entered clinical trials in recent years. These agents are most likely to be effective against resistant strains. We provide a concise review of their structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action and combination regimens.
Assuntos
Antituberculosos/administração & dosagem , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Ensaios Clínicos como Assunto , Descoberta de Drogas , Farmacorresistência Bacteriana , Quimioterapia Combinada , Infecções por HIV/complicações , Humanos , Relação Estrutura-Atividade , Tuberculose/complicações , Tuberculose/epidemiologiaRESUMO
It is estimated that a third of the world's population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.
Assuntos
Antituberculosos/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacocinética , Adamantano/uso terapêutico , Animais , Antituberculosos/química , Antituberculosos/uso terapêutico , Diarilquinolinas , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Etilenodiaminas/química , Etilenodiaminas/farmacocinética , Etilenodiaminas/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Nitroimidazóis/química , Nitroimidazóis/farmacocinética , Nitroimidazóis/uso terapêutico , Oxazóis/química , Oxazóis/farmacocinética , Oxazóis/uso terapêutico , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1â µm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymeraseâ II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.