6oqd | pdb_00006oqd
Crystal structure of Mcl1 with inhibitor 8
Structural highlights
Function[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 PubMedThe prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.,Caenepeel S, Brown SP, Belmontes B, Moody G, Keegan KS, Chui D, Whittington DA, Huang X, Poppe L, Cheng AC, Cardozo M, Houze J, Li Y, Lucas B, Paras NA, Wang X, Taygerly JP, Vimolratana M, Zancanella M, Zhu L, Cajulis E, Osgood T, Sun J, Damon L, Egan RK, Greninger P, McClanaghan JD, Gong J, Moujalled D, Pomilio G, Beltran P, Benes CH, Roberts AW, Huang DC, Wei A, Canon J, Coxon A, Hughes PE Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub , 2018 Sep 25. PMID:30254093[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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