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

Journal Article · · Journal of Medicinal Chemistry
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  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  2. Vanderbilt Univ., Nashville, TN (United States)
  3. Vanderbilt-Ingram Cancer Center, Nashville, TN (United States)
  4. National Cancer Institute, Bethesda, MD (United States)
  5. St. Jude Children’s Research Hospital, Memphis, TN (United States)
  6. Frederick National Lab. for Cancer Research, MD (United States)
+ Show Author Affiliations

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Further, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Cancer Institute (NCI); E. P. Evans Foundation; Biff Ruttenberg Foundation; Vanderbilt-Ingram Cancer Center; Vanderbilt Digestive Disease Research Center
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1515302
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 8 Vol. 62; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (2)

Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers journal September 2019
MCL-1 inhibitors – where are we now (2019)? journal October 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
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