6OVC

hMcl1 inhibitor complex

Summary for 6OVC

• Entry DOI: 10.2210/pdb6ovc/pdb
• Related: 2MHS
• NMR Information: BMRB: 30610
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, (2S)-N-(benzylsulfonyl)-4-(cyclobutylmethyl)-2-(2,4-dichlorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide (2 entities in total)
• Functional Keywords: inhibitor, mcl1 small molecule complex, apoptosis, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 19411.83

Authors

Poppe, L. (deposition date: 2019-05-07, release date: 2019-05-22, Last modification date: 2024-05-01)

Primary citation

Caenepeel, S.,Brown, S.P.,Belmontes, B.,Moody, G.,Keegan, K.S.,Chui, D.,Whittington, D.A.,Huang, X.,Poppe, L.,Cheng, A.C.,Cardozo, M.,Houze, J.,Li, Y.,Lucas, B.,Paras, N.A.,Wang, X.,Taygerly, J.P.,Vimolratana, M.,Zancanella, M.,Zhu, L.,Cajulis, E.,Osgood, T.,Sun, J.,Damon, L.,Egan, R.K.,Greninger, P.,McClanaghan, J.D.,Gong, J.,Moujalled, D.,Pomilio, G.,Beltran, P.,Benes, C.H.,Roberts, A.W.,Huang, D.C.,Wei, A.,Canon, J.,Coxon, A.,Hughes, P.E.
AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.
Cancer Discov, 8:1582-1597, 2018

PubMed Abstract: The 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...

PubMed: 30254093
DOI: 10.1158/2159-8290.CD-18-0387

Experimental method

SOLUTION NMR