AMG 176, a selective MCL1 inhibitor, is effective in hematological 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, DCS; Wei, A; Canon, J; Coxon, A; Hughes, PE

Author(s): 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, DCS; Wei, A; Canon, J; Coxon, A; Hughes, PE;
Details: Publication Year 2018-09-25,Volume 8,Issue #12,Page 1582-1597
Journal Title: Cancer Discovery
Publication Type: Journal Article
Abstract: The prosurvival BCL-2 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 towards apoptosis in subsets of hematological 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 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.
Publisher: AACR
Research Division(s): Cancer And Haematology
PubMed ID: 30254093
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-18-0387
NHMRC Grants: NHMRC/1057742, NHMRC/1016647, NHMRC/1016701,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-10-11 04:23:14

Last Modified: 2020-06-17 09:17:12