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1.
RSC Med Chem ; 13(8): 963-969, 2022 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-36092148

RESUMEN

Overexpression of the anti-apoptotic BCL-2 proteins is associated with the development and progression of a range of cancers. Venetoclax, an FDA-approved BCL-2 inhibitor, is fast becoming the standard-of-care for acute myeloid leukemia and chronic lymphocytic leukemia. However, the median survival offered by venetoclax is only 18 months (as part of a combination therapy regimen), and one of the primary culprits for this is the concomitant upregulation of sister anti-apoptotic proteins, in particular MCL-1 (and BCL-xL), which provides an escape route that manifests as venetoclax resistance. Since inhibition of BCL-xL leads to thrombocytopenia, we believe that a dual MCL-1/BCL-2 inhibitor may provide an enhanced therapeutic effect relative to a selective BCL-2 inhibitor. Beginning with a carboxylic acid-containing literature compound that is a potent inhibitor of MCL-1 and a moderate inhibitor of BCL-2, we herein describe our efforts to develop dual inhibitors of MCL-1 and BCL-2 by scaffold hopping from an indole core to an indazole framework. Subsequently, further elaboration of our novel N2-substituted, indazole-3-carboxylic acid lead into a family of indazole-3-acylsulfonamides resulted in improved inhibition of both MCL-1 and BCL-2, possibly through occupation of the p4 pocket, with minimal or no inhibition of BCL-xL.

2.
ChemMedChem ; 15(18): 1691-1698, 2020 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-32583936

RESUMEN

Protein-protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Unión Proteica/efectos de los fármacos , Conformación Proteica en Hélice alfa/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología
3.
ChemMedChem ; 11(8): 827-33, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-26844930

RESUMEN

The disruption of aberrant protein-protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti-apoptotic Bcl-2 proteins, including myeloid cell leukemia-1 (Mcl-1), and the α-helical Bcl-2 homology-3 (BH3) domains of its pro-apoptotic counterparts, such as Bak. Herein, we describe the discovery of small-molecule inhibitors of the Mcl-1 oncoprotein based on a novel chemotype. Particularly, re-engineering of our α-helix mimetic JY-1-106 into 2,6-di-substituted nicotinates afforded inhibitors of comparable potencies but with significantly decreased molecular weights. The most potent inhibitor 2-(benzyloxy)-6-(4-chloro-3,5-dimethylphenoxy)nicotinic acid (1 r: Ki =2.90 µm) likely binds in the p2 pocket of Mcl-1 and engages R263 in a salt bridge through its carboxylic acid, as supported by 2D (1) H-(15) N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts.


Asunto(s)
Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Benzamidas/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Niacina/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , para-Aminobenzoatos/farmacología , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/química , Benzamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Niacina/síntesis química , Niacina/química , Resonancia Magnética Nuclear Biomolecular , Unión Proteica/efectos de los fármacos , Ingeniería de Proteínas , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-Actividad , Proteína Destructora del Antagonista Homólogo bcl-2/química , para-Aminobenzoatos/química
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