6NE5

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors that Demonstrate in vivo Activity in Mouse Xenograft Models of Human Cancer

Summary for 6NE5

• Entry DOI: 10.2210/pdb6ne5/pdb
• Related: 6BW2
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 3-[(4R)-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]-1-methyl-1H-indole-5-carboxylic acid (3 entities in total)
• Functional Keywords: structure based drug discovery; apoptosis; cancer; mcl-1; drug discovery, apoptosis
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 74988.73

Authors

Zhao, B. (deposition date: 2018-12-17, release date: 2019-04-17, Last modification date: 2023-10-11)

Primary citation

Lee, T.,Christov, P.P.,Shaw, S.,Tarr, J.C.,Zhao, B.,Veerasamy, N.,Jeon, K.O.,Mills, J.J.,Bian, Z.,Sensintaffar, J.L.,Arnold, A.L.,Fogarty, S.A.,Perry, E.,Ramsey, H.E.,Cook, R.S.,Hollingshead, M.,Davis Millin, M.,Lee, K.M.,Koss, B.,Budhraja, A.,Opferman, J.T.,Kim, K.,Arteaga, C.L.,Moore, W.J.,Olejniczak, E.T.,Savona, M.R.,Fesik, S.W.
Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.
J.Med.Chem., 62:3971-3988, 2019

PubMed Abstract: Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

PubMed: 30929420
DOI: 10.1021/acs.jmedchem.8b01991

Experimental method

X-RAY DIFFRACTION (1.85 Å)