8g3y
MBP-Mcl1 in complex with ligand 34MBP-Mcl1 in complex with ligand 34
Structural highlights
FunctionA0A4P1LXE0_SERSF Part of the ABC transporter complex MalEFGK involved in maltose/maltodextrin import. Binds maltose and higher maltodextrins.[RuleBase:RU365005]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 PubMedAvoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model. Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies.,Romanov-Michailidis F, Hsiao CC, Urner LM, Jerhaoui S, Surkyn M, Miller B, Vos A, Dominguez Blanco M, Bueters R, Vinken P, Bekkers M, Walker D, Pietrak B, Eyckmans W, Dores-Sousa JL, Joo Koo S, Lento W, Bauser M, Philippar U, Rombouts FJR J Med Chem. 2023 May 11;66(9):6122-6148. doi: 10.1021/acs.jmedchem.2c01953. Epub , 2023 Apr 28. PMID:37114951[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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