A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment

Qian Cai; Haiying Sun; Yuefeng Peng; Jianfeng Lu; Zaneta Nikolovska-Coleska; Donna McEachern; Liu Liu; Su Qiu; Chao Yie Yang; Rebecca Miller; Han Yi; Tao Zhang; Duxin Sun; Sanmao Kang; Ming Guo; Lance Leopold; Dajun Yang; Shaomeng Wang

doi:10.1021/jm101505d

A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment

Qian Cai
, Haiying Sun
, Yuefeng Peng
, Jianfeng Lu
, Zaneta Nikolovska-Coleska
, Donna McEachern
, Liu Liu
, Su Qiu
, Chao Yie Yang
, Rebecca Miller
, Han Yi
, Tao Zhang
, Duxin Sun
, Sanmao Kang
, Ming Guo
, Lance Leopold
, Dajun Yang
, Shaomeng Wang

Pharmaceutical Sciences

Binghamton University

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

240 Scopus citations

Abstract

We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K_i of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.

Original language	English
Pages (from-to)	2714-2726
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	8
DOIs	https://doi.org/10.1021/jm101505d
State	Published - Apr 28 2011

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Cai, Q., Sun, H., Peng, Y., Lu, J., Nikolovska-Coleska, Z., McEachern, D., Liu, L., Qiu, S., Yang, C. Y., Miller, R., Yi, H., Zhang, T., Sun, D., Kang, S., Guo, M., Leopold, L., Yang, D., & Wang, S. (2011). A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. Journal of Medicinal Chemistry, 54(8), 2714-2726. https://doi.org/10.1021/jm101505d

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title = "A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment",

abstract = "We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with Ki of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.",

author = "Qian Cai and Haiying Sun and Yuefeng Peng and Jianfeng Lu and Zaneta Nikolovska-Coleska and Donna McEachern and Liu Liu and Su Qiu and Yang, \{Chao Yie\} and Rebecca Miller and Han Yi and Tao Zhang and Duxin Sun and Sanmao Kang and Ming Guo and Lance Leopold and Dajun Yang and Shaomeng Wang",

year = "2011",

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doi = "10.1021/jm101505d",

language = "English",

volume = "54",

pages = "2714--2726",

journal = "Journal of Medicinal Chemistry",

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Cai, Q, Sun, H, Peng, Y, Lu, J, Nikolovska-Coleska, Z, McEachern, D, Liu, L, Qiu, S, Yang, CY, Miller, R, Yi, H, Zhang, T, Sun, D, Kang, S, Guo, M, Leopold, L, Yang, D & Wang, S 2011, 'A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment', Journal of Medicinal Chemistry, vol. 54, no. 8, pp. 2714-2726. https://doi.org/10.1021/jm101505d

TY - JOUR

T1 - A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment

AU - Cai, Qian

AU - Sun, Haiying

AU - Peng, Yuefeng

AU - Lu, Jianfeng

AU - Nikolovska-Coleska, Zaneta

AU - McEachern, Donna

AU - Liu, Liu

AU - Qiu, Su

AU - Yang, Chao Yie

AU - Miller, Rebecca

AU - Yi, Han

AU - Zhang, Tao

AU - Sun, Duxin

AU - Kang, Sanmao

AU - Guo, Ming

AU - Leopold, Lance

AU - Yang, Dajun

AU - Wang, Shaomeng

PY - 2011/4/28

Y1 - 2011/4/28

N2 - We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with Ki of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.

AB - We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with Ki of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.

UR - https://www.scopus.com/pages/publications/79954504195

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DO - 10.1021/jm101505d

M3 - Article

C2 - 21443232

SN - 0022-2623

VL - 54

SP - 2714

EP - 2726

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment

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