9PW7

Myeloid cell leukemia-1 (Mcl-1) complexed with compound 13

これはPDB形式変換不可エントリーです。

9PW7 の概要

• エントリーDOI: 10.2210/pdb9pw7/pdb
• 分子名称: Maltodextrin-binding protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (2S,4R,5S,12P,23R)-11-chloro-7-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-27,28-dimethoxy-4,15-dimethyl-32-oxo-19-oxa-2,5,15,16,23-pentaazaheptacyclo[21.6.1.1~2,6~.1~5,8~.0~12,31~.0~13,17~.0~26,30~]dotriaconta-1(30),6,8(31),9,11,13,16,24,26,28-decaene-24-carboxylic acid (non-preferred name), ... (4 entities in total)
• 機能のキーワード: mcl-1, cancer, drug discovery, fbdd, apoptosis
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58557.09

構造登録者

Zhao, B.,Fesik, S.W. (登録日: 2025-08-04, 公開日: 2025-09-17)

主引用文献

Tarr, J.C.,Jeon, K.,Veerasamy, N.,Aichinger, M.,Salovich, J.M.,Zhao, B.,Sensintaffar, J.L.,Arnhof, H.,Wunberg, T.,Sgubin, D.,Arnold, A.,Vekariya, R.H.,Christov, P.P.,Kim, K.,Fuchs, J.E.,Karier, P.,Betzemeier, B.,Van Meveren, M.,Miriyala, N.,Olejniczak, E.T.,Engelhardt, H.,Lee, T.,McConnell, D.,Fesik, S.W.
Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model.
J.Med.Chem., 68:18553-18578, 2025

PubMed Abstract: The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the ()-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.

PubMed: 40864607
DOI: 10.1021/acs.jmedchem.5c01376

実験手法

X-RAY DIFFRACTION (1.95 Å)