8g3u

From Proteopedia

MBP-Mcl1 in complex with ligand 21

Structural highlights

8g3u is a 1 chain structure with sequence from Homo sapiens and Serratia sp. FS14. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.94Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A0A4P1LXE0_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 PubMed

Avoidance 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

↑ Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000 Jul 21;275(29):22136-46. PMID:10766760 doi:10.1074/jbc.M909572199
↑ 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. Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies. J Med Chem. 2023 May 11;66(9):6122-6148. PMID:37114951 doi:10.1021/acs.jmedchem.2c01953