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MBP-Mcl1 in complex with ligand 10MBP-Mcl1 in complex with ligand 10
Structural highlights
FunctionMALE_ECO57 Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity).MCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[1] Publication Abstract from PubMedMyeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (R(a))-10 and (R(a))-15, possessing remarkable cellular potency and properties. Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.,Demin S, Peschiulli A, Velter AI, Vos A, De Boeck B, Miller B, Rombouts FJR, Reuillon T, Lento W, Blanco MD, Jouffroy M, Steyvers H, Bekkers M, Altrocchi C, Pietrak B, Koo SJ, Szewczuk L, Attar R, Philippar U ACS Med Chem Lett. 2023 Jul 3;14(7):955-961. doi: 10.1021/acsmedchemlett.3c00141. , eCollection 2023 Jul 13. PMID:37465311[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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