Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening

Zachary Miller; Keun Sik Kim; Do Min Lee; Vinod Kasam; Si Eun Baek; Kwang Hyun Lee; Yan Yan Zhang; Lin Ao; Kimberly Carmony; Na Ra Lee; Shou Zhou; Qingquan Zhao; Yujin Jang; Hyun Young Jeong; Chang Guo Zhan; Wooin Lee; Dong Eun Kim; Kyung Bo Kim

doi:10.1021/jm501344n

Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening

Zachary Miller
, Keun Sik Kim
, Do Min Lee
, Vinod Kasam
, Si Eun Baek
, Kwang Hyun Lee
, Yan Yan Zhang
, Lin Ao
, Kimberly Carmony
, Na Ra Lee
, Shou Zhou
, Qingquan Zhao
, Yujin Jang
, Hyun Young Jeong
, Chang Guo Zhan
, Wooin Lee
, Dong Eun Kim
, Kyung Bo Kim

Pharmaceutical Sciences

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

47 Scopus citations

Abstract

We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

Original language	English
Pages (from-to)	2036-2041
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	4
DOIs	https://doi.org/10.1021/jm501344n
State	Published - Feb 26 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Funding

Funders	Funder number
National Institutes of Health (NIH)	R01 CA128903, R15 CA156601
National Research Foundation of Korea	2011-0016385
National Childhood Cancer Registry – National Cancer Institute	R01CA128903
National Childhood Cancer Registry – National Cancer Institute

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm501344n

Cite this

Miller, Z., Kim, K. S., Lee, D. M., Kasam, V., Baek, S. E., Lee, K. H., Zhang, Y. Y., Ao, L., Carmony, K., Lee, N. R., Zhou, S., Zhao, Q., Jang, Y., Jeong, H. Y., Zhan, C. G., Lee, W., Kim, D. E., & Kim, K. B. (2015). Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening. Journal of Medicinal Chemistry, 58(4), 2036-2041. https://doi.org/10.1021/jm501344n

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title = "Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening",

abstract = "We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.",

author = "Zachary Miller and Kim, \{Keun Sik\} and Lee, \{Do Min\} and Vinod Kasam and Baek, \{Si Eun\} and Lee, \{Kwang Hyun\} and Zhang, \{Yan Yan\} and Lin Ao and Kimberly Carmony and Lee, \{Na Ra\} and Shou Zhou and Qingquan Zhao and Yujin Jang and Jeong, \{Hyun Young\} and Zhan, \{Chang Guo\} and Wooin Lee and Kim, \{Dong Eun\} and Kim, \{Kyung Bo\}",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

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doi = "10.1021/jm501344n",

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AU - Kim, Keun Sik

AU - Lee, Do Min

AU - Kasam, Vinod

AU - Baek, Si Eun

AU - Lee, Kwang Hyun

AU - Zhang, Yan Yan

AU - Ao, Lin

AU - Carmony, Kimberly

AU - Lee, Na Ra

AU - Zhou, Shou

AU - Zhao, Qingquan

AU - Jang, Yujin

AU - Jeong, Hyun Young

AU - Zhan, Chang Guo

AU - Lee, Wooin

AU - Kim, Dong Eun

AU - Kim, Kyung Bo

PY - 2015/2/26

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N2 - We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

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Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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