Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency

Chia Hsien Wu; Mohane Selvaraj Coumar; Chang Ying Chu; Wen Hsing Lin; Yi Rong Chen; Chiung Tong Chen; Hui Yi Shiao; Shaik Rafi; Sing Yi Wang; Hui Hsu; Chun Hwa Chen; Chun Yu Chang; Teng Yuan Chang; Tzu Wen Lien; Ming Yu Fang; Kai Chia Yeh; Ching Ping Chen; Teng Kuang Yeh; Su Huei Hsieh; John T.A. Hsu; Chun Chen Liao; Yu Sheng Chao; Hsing Pang Hsieh

doi:10.1021/jm100607r

Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency

Chia Hsien Wu, Mohane Selvaraj Coumar, Chang Ying Chu, Wen Hsing Lin, Yi Rong Chen, Chiung Tong Chen, Hui Yi Shiao, Shaik Rafi, Sing Yi Wang, Hui Hsu, Chun Hwa Chen, Chun Yu Chang, Teng Yuan Chang, Tzu Wen Lien, Ming Yu Fang, Kai Chia Yeh, Ching Ping Chen, Teng Kuang Yeh, Su Huei Hsieh, John T.A. HsuChun Chen Liao, Yu Sheng Chao, Hsing Pang Hsieh

Center of Applied Nanomedicine

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114 Citations (Scopus)

Abstract

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

Original language	English
Pages (from-to)	7316-7326
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	20
DOIs	https://doi.org/10.1021/jm100607r
Publication status	Published - 2010 Oct 28

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Wu, C. H., Coumar, M. S., Chu, C. Y., Lin, W. H., Chen, Y. R., Chen, C. T., Shiao, H. Y., Rafi, S., Wang, S. Y., Hsu, H., Chen, C. H., Chang, C. Y., Chang, T. Y., Lien, T. W., Fang, M. Y., Yeh, K. C., Chen, C. P., Yeh, T. K., Hsieh, S. H., ... Hsieh, H. P. (2010). Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency. Journal of Medicinal Chemistry, 53(20), 7316-7326. https://doi.org/10.1021/jm100607r

@article{6647c6bd3a3648b09d385562af659d9e,

title = "Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency",

abstract = "HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.",

author = "Wu, {Chia Hsien} and Coumar, {Mohane Selvaraj} and Chu, {Chang Ying} and Lin, {Wen Hsing} and Chen, {Yi Rong} and Chen, {Chiung Tong} and Shiao, {Hui Yi} and Shaik Rafi and Wang, {Sing Yi} and Hui Hsu and Chen, {Chun Hwa} and Chang, {Chun Yu} and Chang, {Teng Yuan} and Lien, {Tzu Wen} and Fang, {Ming Yu} and Yeh, {Kai Chia} and Chen, {Ching Ping} and Yeh, {Teng Kuang} and Hsieh, {Su Huei} and Hsu, {John T.A.} and Liao, {Chun Chen} and Chao, {Yu Sheng} and Hsieh, {Hsing Pang}",

year = "2010",

month = oct,

day = "28",

doi = "10.1021/jm100607r",

language = "English",

volume = "53",

pages = "7316--7326",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "20",

}

Wu, CH, Coumar, MS, Chu, CY, Lin, WH, Chen, YR, Chen, CT, Shiao, HY, Rafi, S, Wang, SY, Hsu, H, Chen, CH, Chang, CY, Chang, TY, Lien, TW, Fang, MY, Yeh, KC, Chen, CP, Yeh, TK, Hsieh, SH, Hsu, JTA, Liao, CC, Chao, YS & Hsieh, HP 2010, 'Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency', Journal of Medicinal Chemistry, vol. 53, no. 20, pp. 7316-7326. https://doi.org/10.1021/jm100607r

Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency. / Wu, Chia Hsien; Coumar, Mohane Selvaraj; Chu, Chang Ying et al.
In: Journal of Medicinal Chemistry, Vol. 53, No. 20, 28.10.2010, p. 7316-7326.

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

TY - JOUR

T1 - Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors

T2 - The role of side chain chirality and michael acceptor group for maximal potency

AU - Wu, Chia Hsien

AU - Coumar, Mohane Selvaraj

AU - Chu, Chang Ying

AU - Lin, Wen Hsing

AU - Chen, Yi Rong

AU - Chen, Chiung Tong

AU - Shiao, Hui Yi

AU - Rafi, Shaik

AU - Wang, Sing Yi

AU - Hsu, Hui

AU - Chen, Chun Hwa

AU - Chang, Chun Yu

AU - Chang, Teng Yuan

AU - Lien, Tzu Wen

AU - Fang, Ming Yu

AU - Yeh, Kai Chia

AU - Chen, Ching Ping

AU - Yeh, Teng Kuang

AU - Hsieh, Su Huei

AU - Hsu, John T.A.

AU - Liao, Chun Chen

AU - Chao, Yu Sheng

AU - Hsieh, Hsing Pang

PY - 2010/10/28

Y1 - 2010/10/28

N2 - HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

AB - HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

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U2 - 10.1021/jm100607r

DO - 10.1021/jm100607r

M3 - Article

C2 - 20961149

AN - SCOPUS:77958465100

SN - 0022-2623

VL - 53

SP - 7316

EP - 7326

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency

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