Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design

Shaw, Subrata; Bian, Zhiguo; Zhao, Bin; Tarr, James C.; Veerasamy, Nagarathanam; Jeon, Kyu Ok; Belmar, Johannes; Arnold, Allison L.; Fogarty, Stuart A.; Perry, Evan; Sensintaffar, John L.; Camper, DeMarco V.; Rossanese, Olivia W.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.7b01155

Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design

Journal Article · Thu Jan 11 00:00:00 EST 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b01155· OSTI ID:1433690

Shaw, Subrata ^[1]; Bian, Zhiguo ^[1]; Zhao, Bin ^[1]; Tarr, James C. ^[1]; Veerasamy, Nagarathanam ^[1]; Jeon, Kyu Ok ^[1]; Belmar, Johannes ^[1]; Arnold, Allison L. ^[1]; Fogarty, Stuart A. ^[1]; Perry, Evan ^[1]; Sensintaffar, John L. ^[1]; Camper, DeMarco V. ^[1]; Rossanese, Olivia W. ^[1]; Lee, Taekyu ^[1]; Olejniczak, Edward T. ^[1]; ^[1]

Vanderbilt Univ. School of Medicine, Nashville, TN (United States)

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Furthermore, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Leidos Biomed Prime; NCI SPORE; National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1433690

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 6 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design

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