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

Taekyu Lee, Plamen P. Christov, Subrata Shaw, James C. Tarr, Bin Zhao, Nagarathanam Veerasamy, Kyu Ok Jeon, Jonathan J. Mills, Zhiguo Bian, John L. Sensintaffar, Allison L. Arnold, Stuart A. Fogarty, Evan Perry, Haley E. Ramsey, Rebecca S. Cook, Melinda Hollingshead, Myrtle Davis Millin, Kyung Min Lee, Brian Koss, Amit BudhrajaJoseph T. Opferman, Kwangho Kim, Carlos L Arteaga, William J. Moore, Edward T. Olejniczak, Michael R. Savona, Stephen W. Fesik

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3971-3988
Number of pages18
JournalJournal of Medicinal Chemistry
Volume62
Issue number8
DOIs
StatePublished - Apr 25 2019
Externally publishedYes

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Myeloid Leukemia
Myeloid Cells
Heterografts
Neoplasms
Triple Negative Breast Neoplasms
Apoptosis
Proteasome Inhibitors
B-Cell Lymphoma
Growth
Tumor Cell Line
Animal Models
Cell Culture Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer. / Lee, Taekyu; Christov, Plamen P.; Shaw, Subrata; Tarr, James C.; Zhao, Bin; Veerasamy, Nagarathanam; Jeon, Kyu Ok; Mills, Jonathan J.; Bian, Zhiguo; Sensintaffar, John L.; Arnold, Allison L.; Fogarty, Stuart A.; Perry, Evan; Ramsey, Haley E.; Cook, Rebecca S.; Hollingshead, Melinda; Davis Millin, Myrtle; Lee, Kyung Min; Koss, Brian; Budhraja, Amit; Opferman, Joseph T.; Kim, Kwangho; Arteaga, Carlos L; Moore, William J.; Olejniczak, Edward T.; Savona, Michael R.; Fesik, Stephen W.

In: Journal of Medicinal Chemistry, Vol. 62, No. 8, 25.04.2019, p. 3971-3988.

Research output: Contribution to journalArticle

Lee, T, Christov, PP, Shaw, S, Tarr, JC, Zhao, B, Veerasamy, N, Jeon, KO, Mills, JJ, Bian, Z, Sensintaffar, JL, Arnold, AL, Fogarty, SA, Perry, E, Ramsey, HE, Cook, RS, Hollingshead, M, Davis Millin, M, Lee, KM, Koss, B, Budhraja, A, Opferman, JT, Kim, K, Arteaga, CL, Moore, WJ, Olejniczak, ET, Savona, MR & Fesik, SW 2019, 'Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer', Journal of Medicinal Chemistry, vol. 62, no. 8, pp. 3971-3988. https://doi.org/10.1021/acs.jmedchem.8b01991
Lee, Taekyu ; Christov, Plamen P. ; Shaw, Subrata ; Tarr, James C. ; Zhao, Bin ; Veerasamy, Nagarathanam ; Jeon, Kyu Ok ; Mills, Jonathan J. ; Bian, Zhiguo ; Sensintaffar, John L. ; Arnold, Allison L. ; Fogarty, Stuart A. ; Perry, Evan ; Ramsey, Haley E. ; Cook, Rebecca S. ; Hollingshead, Melinda ; Davis Millin, Myrtle ; Lee, Kyung Min ; Koss, Brian ; Budhraja, Amit ; Opferman, Joseph T. ; Kim, Kwangho ; Arteaga, Carlos L ; Moore, William J. ; Olejniczak, Edward T. ; Savona, Michael R. ; Fesik, Stephen W. / Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 8. pp. 3971-3988.
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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.",
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AU - Lee, Taekyu

AU - Christov, Plamen P.

AU - Shaw, Subrata

AU - Tarr, James C.

AU - Zhao, Bin

AU - Veerasamy, Nagarathanam

AU - Jeon, Kyu Ok

AU - Mills, Jonathan J.

AU - Bian, Zhiguo

AU - Sensintaffar, John L.

AU - Arnold, Allison L.

AU - Fogarty, Stuart A.

AU - Perry, Evan

AU - Ramsey, Haley E.

AU - Cook, Rebecca S.

AU - Hollingshead, Melinda

AU - Davis Millin, Myrtle

AU - Lee, Kyung Min

AU - Koss, Brian

AU - Budhraja, Amit

AU - Opferman, Joseph T.

AU - Kim, Kwangho

AU - Arteaga, Carlos L

AU - Moore, William J.

AU - Olejniczak, Edward T.

AU - Savona, Michael R.

AU - Fesik, Stephen W.

PY - 2019/4/25

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N2 - 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.

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