Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

Karson J. Kump; Lei Miao; Ahmed S.A. Mady; Nurul H. Ansari; Uttar K. Shrestha; Yuting Yang; Mohan Pal; Chenzhong Liao; Andrej Perdih; Fardokht A. Abulwerdi; Krishnapriya Chinnaswamy; Jennifer L. Meagher; Jacob M. Carlson; May Khanna; Jeanne A. Stuckey; Zaneta Nikolovska-Coleska

doi:10.1021/acs.jmedchem.9b01442

Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

Karson J. Kump, Lei Miao, Ahmed S.A. Mady, Nurul H. Ansari, Uttar K. Shrestha, Yuting Yang, Mohan Pal, Chenzhong Liao, Andrej Perdih, Fardokht A. Abulwerdi, Krishnapriya Chinnaswamy, Jennifer L. Meagher, Jacob M. Carlson, May Khanna, Jeanne A. Stuckey, Zaneta Nikolovska-Coleska

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with K_i values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

Original language	English (US)
Pages (from-to)	2489-2510
Number of pages	22
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	5
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01442
State	Published - Mar 12 2020

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.9b01442

Cite this

Kump, K. J., Miao, L., Mady, A. S. A., Ansari, N. H., Shrestha, U. K., Yang, Y., Pal, M., Liao, C., Perdih, A., Abulwerdi, F. A., Chinnaswamy, K., Meagher, J. L., Carlson, J. M., Khanna, M., Stuckey, J. A., & Nikolovska-Coleska, Z. (2020). Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins. Journal of Medicinal Chemistry, 63(5), 2489-2510. https://doi.org/10.1021/acs.jmedchem.9b01442

Kump, KJ, Miao, L, Mady, ASA, Ansari, NH, Shrestha, UK, Yang, Y, Pal, M, Liao, C, Perdih, A, Abulwerdi, FA, Chinnaswamy, K, Meagher, JL, Carlson, JM, Khanna, M, Stuckey, JA & Nikolovska-Coleska, Z 2020, 'Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins', Journal of Medicinal Chemistry, vol. 63, no. 5, pp. 2489-2510. https://doi.org/10.1021/acs.jmedchem.9b01442

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title = "Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins",

abstract = "Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.",

author = "Kump, {Karson J.} and Lei Miao and Mady, {Ahmed S.A.} and Ansari, {Nurul H.} and Shrestha, {Uttar K.} and Yuting Yang and Mohan Pal and Chenzhong Liao and Andrej Perdih and Abulwerdi, {Fardokht A.} and Krishnapriya Chinnaswamy and Meagher, {Jennifer L.} and Carlson, {Jacob M.} and May Khanna and Stuckey, {Jeanne A.} and Zaneta Nikolovska-Coleska",

note = "Funding Information: This work was supported by the NIH R01 CA-149442, CA-217141 and HL-13982401, R21 NS056915 grants, Harrington Discovery Award AACR Bayer Innovation and Discovery Award, and the MTRAC Fast Forward Medical Innovation Award to Z.N.-C.; NIH Training Program in Translational Research (T32-GM113900) and Rackham Merit Fellowship to K.J.K.; Advanced Proteome Informatics of Cancer (T32 CA140044) to A.S.A.M.; the bilateral research grant (BI/US/18-20-068) funded by the Slovenian Research Agency between the National Institute of Chemistry, Slovenia, and the University of Michigan, as well as the P1-0012 core research grant from Slovenian Research Agency funded the research visit of A.P. to the University of Michigan in the lab of Z.N.-C. Z.N.-C. and J.A.S. are grateful for the support of this work from NIH P30 CA046592. We kindly thank W. Clay Brown from the U-M Center for Structural Biology for providing expression vectors. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817). Funding Information: This work was supported by the NIH R01 CA-149442, CA-217141, and HL-13982401, R21 NS056915 grants, Harrington Discovery Award, AACR Bayer Innovation and Discovery Award, and the MTRAC Fast Forward Medical Innovation Award to Z.N.-C.; NIH Training Program in Translational Research (T32-GM113900) and Rackham Merit Fellowship to K.J.K.; Advanced Proteome Informatics of Cancer (T32 CA140044) to A.S.A.M.; the bilateral research grant (BI/US/18-20-068) funded by the Slovenian Research Agency between the National Institute of Chemistry, Slovenia, and the University of Michigan, as well as the P1-0012 core research grant from Slovenian Research Agency funded the research visit of A.P. to the University of Michigan in the lab of Z.N.-C. Z.N.-C. and J.A.S. are grateful for the support of this work from NIH P30 CA046592. We kindly thank W. Clay Brown from the U-M Center for Structural Biology for providing expression vectors. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817). Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = mar,

day = "12",

doi = "10.1021/acs.jmedchem.9b01442",

language = "English (US)",

volume = "63",

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T1 - Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

AU - Kump, Karson J.

AU - Miao, Lei

AU - Mady, Ahmed S.A.

AU - Ansari, Nurul H.

AU - Shrestha, Uttar K.

AU - Yang, Yuting

AU - Pal, Mohan

AU - Liao, Chenzhong

AU - Perdih, Andrej

AU - Abulwerdi, Fardokht A.

AU - Chinnaswamy, Krishnapriya

AU - Meagher, Jennifer L.

AU - Carlson, Jacob M.

AU - Khanna, May

AU - Stuckey, Jeanne A.

AU - Nikolovska-Coleska, Zaneta

N1 - Funding Information: This work was supported by the NIH R01 CA-149442, CA-217141 and HL-13982401, R21 NS056915 grants, Harrington Discovery Award AACR Bayer Innovation and Discovery Award, and the MTRAC Fast Forward Medical Innovation Award to Z.N.-C.; NIH Training Program in Translational Research (T32-GM113900) and Rackham Merit Fellowship to K.J.K.; Advanced Proteome Informatics of Cancer (T32 CA140044) to A.S.A.M.; the bilateral research grant (BI/US/18-20-068) funded by the Slovenian Research Agency between the National Institute of Chemistry, Slovenia, and the University of Michigan, as well as the P1-0012 core research grant from Slovenian Research Agency funded the research visit of A.P. to the University of Michigan in the lab of Z.N.-C. Z.N.-C. and J.A.S. are grateful for the support of this work from NIH P30 CA046592. We kindly thank W. Clay Brown from the U-M Center for Structural Biology for providing expression vectors. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817). Funding Information: This work was supported by the NIH R01 CA-149442, CA-217141, and HL-13982401, R21 NS056915 grants, Harrington Discovery Award, AACR Bayer Innovation and Discovery Award, and the MTRAC Fast Forward Medical Innovation Award to Z.N.-C.; NIH Training Program in Translational Research (T32-GM113900) and Rackham Merit Fellowship to K.J.K.; Advanced Proteome Informatics of Cancer (T32 CA140044) to A.S.A.M.; the bilateral research grant (BI/US/18-20-068) funded by the Slovenian Research Agency between the National Institute of Chemistry, Slovenia, and the University of Michigan, as well as the P1-0012 core research grant from Slovenian Research Agency funded the research visit of A.P. to the University of Michigan in the lab of Z.N.-C. Z.N.-C. and J.A.S. are grateful for the support of this work from NIH P30 CA046592. We kindly thank W. Clay Brown from the U-M Center for Structural Biology for providing expression vectors. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817). Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/3/12

Y1 - 2020/3/12

N2 - Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

AB - Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

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Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

Abstract

ASJC Scopus subject areas

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The crystal structure of anti-apoptotic Mcl-1 protein in complex with 2, 5-substituted benzoic acid inhibitor 21

Mcl-1 bound to compound 24

Mcl-1 bound to compound 19

Cite this

Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Datasets

The crystal structure of anti-apoptotic Mcl-1 protein in complex with 2, 5-substituted benzoic acid inhibitor 21

Mcl-1 bound to compound 24

Mcl-1 bound to compound 19

Cite this