X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor

Younho Lee; Hyunkyung Kim; Haelee Kim; Ha Yeon Cho; Jun Goo Jee; Kyung Ah Seo; Jung Beom Son; Eunhwa Ko; Hwan Geun Choi; Nam Doo Kim; Ikyon Kim

doi:10.1021/acs.jmedchem.1c00542

X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor

Younho Lee, Hyunkyung Kim, Haelee Kim, Ha Yeon Cho, Jun Goo Jee, Kyung Ah Seo, Jung Beom Son, Eunhwa Ko, Hwan Geun Choi, Nam Doo Kim, Ikyon Kim

Department of Pharmacy

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

3 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.

Original language	English
Pages (from-to)	6985-6995
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	10
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00542
Publication status	Published - 2021 May 27

Bibliographical note

Funding Information:
We thank the National Research Foundation of Korea (NRF-2018R1A6A1A03023718 and NRF-2020R1A2C2005961 to I.K.) for generous financial support.

Publisher Copyright:
© 2021 American Chemical Society.

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.1c00542

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Lee, Y., Kim, H., Kim, H., Cho, H. Y., Jee, J. G., Seo, K. A., Son, J. B., Ko, E., Choi, H. G., Kim, N. D., & Kim, I. (2021). X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor. Journal of Medicinal Chemistry, 64(10), 6985-6995. https://doi.org/10.1021/acs.jmedchem.1c00542

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title = "X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor",

abstract = "Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.",

author = "Younho Lee and Hyunkyung Kim and Haelee Kim and Cho, {Ha Yeon} and Jee, {Jun Goo} and Seo, {Kyung Ah} and Son, {Jung Beom} and Eunhwa Ko and Choi, {Hwan Geun} and Kim, {Nam Doo} and Ikyon Kim",

note = "Funding Information: We thank the National Research Foundation of Korea (NRF-2018R1A6A1A03023718 and NRF-2020R1A2C2005961 to I.K.) for generous financial support. Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

month = may,

day = "27",

doi = "10.1021/acs.jmedchem.1c00542",

language = "English",

volume = "64",

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Lee, Y, Kim, H, Kim, H, Cho, HY, Jee, JG, Seo, KA, Son, JB, Ko, E, Choi, HG, Kim, ND & Kim, I 2021, 'X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor', Journal of Medicinal Chemistry, vol. 64, no. 10, pp. 6985-6995. https://doi.org/10.1021/acs.jmedchem.1c00542

TY - JOUR

T1 - X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor

AU - Lee, Younho

AU - Kim, Hyunkyung

AU - Kim, Haelee

AU - Cho, Ha Yeon

AU - Jee, Jun Goo

AU - Seo, Kyung Ah

AU - Son, Jung Beom

AU - Ko, Eunhwa

AU - Choi, Hwan Geun

AU - Kim, Nam Doo

AU - Kim, Ikyon

N1 - Funding Information: We thank the National Research Foundation of Korea (NRF-2018R1A6A1A03023718 and NRF-2020R1A2C2005961 to I.K.) for generous financial support. Publisher Copyright: © 2021 American Chemical Society.

PY - 2021/5/27

Y1 - 2021/5/27

N2 - Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.

AB - Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.

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ER -

X-ray Crystal Structure-Guided Design and Optimization of 7 H-Pyrrolo[2,3- d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor

Abstract

Bibliographical note

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