6OVC

hMcl1 inhibitor complex

6OVC の概要

• エントリーDOI: 10.2210/pdb6ovc/pdb
• 関連するPDBエントリー: 2MHS
• NMR情報: BMRB: 30610
• 分子名称: 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)
• 機能のキーワード: inhibitor, mcl1 small molecule complex, apoptosis, apoptosis-inhibitor complex, apoptosis/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19411.83

構造登録者

Poppe, L. (登録日: 2019-05-07, 公開日: 2019-05-22, 最終更新日: 2024-05-01)

主引用文献

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

実験手法

SOLUTION NMR