9BCG

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

This is a non-PDB format compatible entry.

Summary for 9BCG

• Entry DOI: 10.2210/pdb9bcg/pdb
• Related PRD ID: PRD_900001
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, 7-[(4R,5S,6P)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl]-4,5-dimethoxy-1-methyl-1H-indole-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: mcl-1, drug discovery, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 58283.74

Authors

Zhao, B.,Fesik, S.W. (deposition date: 2024-04-09, release date: 2024-08-07, Last modification date: 2024-09-11)

Primary citation

Tarr, J.C.,Salovich, J.M.,Aichinger, M.,Jeon, K.,Veerasamy, N.,Sensintaffar, J.L.,Arnhof, H.,Samwer, M.,Christov, P.P.,Kim, K.,Wunberg, T.,Schweifer, N.,Trapani, F.,Arnold, A.,Martin, F.,Zhao, B.,Miriyala, N.,Sgubin, D.,Fogarty, S.,Moore, W.J.,Stott, G.M.,Olejniczak, E.T.,Engelhardt, H.,Rudolph, D.,Lee, T.,McConnell, D.B.,Fesik, S.W.
Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors.
J.Med.Chem., 67:14370-14393, 2024

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound , that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

PubMed: 39102508
DOI: 10.1021/acs.jmedchem.4c01188

Experimental method

X-RAY DIFFRACTION (1.898 Å)