8T6F

Crystal structure of human MBP-Myeloid cell leukemia 1 (Mcl-1) in complex with BRD810 inhibitor

8T6F の概要

• エントリーDOI: 10.2210/pdb8t6f/pdb
• 分子名称: Maltose/maltodextrin-binding periplasmic protein/Induced myeloid leukemia cell differentiation protein Mcl-1 Chimera, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: inhibitor, mcl1, mbp-fusion, brd810, apoptosis
• 由来する生物種: Escherichia coli K-12; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58609.03

構造登録者

Poncet-Montange, G.,Lemke, C.T. (登録日: 2023-06-15, 公開日: 2024-06-19, 最終更新日: 2024-11-06)

主引用文献

Rauh, U.,Wei, G.,Serrano-Wu, M.,Kosmidis, G.,Kaulfuss, S.,Siegel, F.,Thede, K.,McFarland, J.,Lemke, C.T.,Werbeck, N.,Nowak-Reppel, K.,Pilari, S.,Menz, S.,Ocker, M.,Zhang, W.,Davis, K.,Poncet-Montange, G.,Roth, J.,Daniels, D.,Kaushik, V.K.,Hubbard, B.,Ziegelbauer, K.,Golub, T.R.
BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.
Nat Cancer, 5:1479-1493, 2024

PubMed Abstract: The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.

PubMed: 39179926
DOI: 10.1038/s43018-024-00814-0

実験手法

X-RAY DIFFRACTION (1.56 Å)