Discovery of a Novel, Highly Potent, and Selective Thieno[3,2- d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent

Article abstract of DOI:10.1021/acs.jmedchem.9b01427

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.

Full text of DOI:10.1021/acs.jmedchem.9b01427

Subscriber access provided by BIU Pharmacie | Faculté de Pharmacie, Université Paris V
Article
Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-
Based Cdc7 inhibitor with a Quinuclidine Moiety (TAK-931)
as an Orally Active Investigational Anti-Tumor Agent
Osamu Kurasawa, Tohru Miyazaki, Misaki Homma, Yuya Oguro, Takashi Imada, Noriko Uchiyama,
Kenichi Iwai, Yukiko Yamamoto, Momoko Ohori, Hideto Hara, Hiroshi Sugimoto, Kentaro
Iwata, Robert Skene, Isaac D. Hoffman, Akihiro Ohashi, Toshiyuki Nomura, and Nobuo Cho
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b01427 • Publication Date (Web): 02 Jan 2020
Downloaded from pubs.acs.org on January 2, 2020
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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ACS Paragon Plus Environment

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Journal of Medicinal Chemistry
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