Noriaki Uesaka

Synthetic studies on selective adenosine A2A receptor antagonists. Part II: Synthesis and structure–activity relationships of novel benzofuran derivatives

A series of benzofuran derivatives were prepared to study their antagonistic activities to the A(2A) receptor. Replacement of the ester group of the lead compound 1 with phenyl ring improved the PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds 13c, 13f, and 24a showed good potency in vitro and were identified as novel A(2A) receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.

Abstract 2715: Discovery and characterization of a highly potent Wnt/ β -catenin pathway inhibitor targeting tankyrase

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Wnt/β-catenin pathway controls many biological processes including cell proliferation and tissue development. In Wnt pathway, β-catenin is a key downstream factor which interacts with transcription factor T-cell factor (TCF) in the nucleus and induces expression of TCF responsive genes. β-catenin degradation is promoted by a cytoplasmic complex of APC, Axin and GSK3β. In many cancers, constitutive activation of Wnt/β-catenin pathway is observed due to mutations of the related genes and overexpression of Wnt ligands and receptors. For example, truncating mutation of the tumor suppressor APC are the most prevalent in colon cancer. APC deficiency leads to accumulation of nuclear β-catenin and promotes the transcription of downstream target genes. Hence, Wnt/β-catenin pathway inhibitor can be an attractive therapeutic agent for cancer patients. Results: To screen for Wnt/β-catenin pathway inhibitor, a reporter-based screen using a colon cancer cell line harboring APC mutation was performed. We identified a Wnt/β-catenin pathway inhibitor K-756 with an IC50 of 110 nmol/L, which was a distinct chemical structure from previously reported Wnt/β-catenin pathway inhibitors. From target identification study, it became clear that K-756 was a selective tankyrase inhibitor (AACR-NCI-EORTC 2013). Further development of the derivatives of K-756 using a structure-based drug design approach led to synthesis of K-476. K-476 inhibited Wnt/β-catenin pathway in APC mutant DLD-1 cell line with an IC50 of 0.3 nmol/L. K-476 stabilized Axin proteins and decreased active β-catenin. Wnt downstream target gene inhibition was also observed by K-476. PARP family profile assay was performed to evaluate the selectivity of K-476. K-476 inhibited tankyrase 1 and 2 and did not inhibit other PARP family isoforms even at 1000 nmol/L. Kinase profile assay was also performed towards 448 kinase but K-476 did not inhibit any of the kinases at 1000 nmol/L. Therefore K-476 is a highly selective tankyrase inhibitor. K-476 inhibited Wnt pathway signal and cell growth in colon cancer cell lines with an GI50 of less than 5 nmol/L. Oral dosing of K-476 resulted in inhibition of the reporter activity and Wnt downstream genes in a colon cancer xenograft mouse model. Taken together, K-476 represents a highly potent tankyrase inhibitor and is anticipated to be an important compound for further development of antitumor agent targeting the Wnt/β-catenin pathway regulation. Citation Format: Ryoko Okada, Yuichi Takahashi, Keiichi Motosawa, Yasuo Watanabe, Asae Igarashi, Ran Okada, Masahiro Ikkaku, Hikaru Miyagi, Yusuke Miura, Kazuki Asanome, Noriaki Uesaka, Jun-ichi Saito, Hiroshi Ishida, Ryuichiro Nakai. Discovery and characterization of a highly potent Wnt/ β -catenin pathway inhibitor targeting tankyrase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2715. doi:10.1158/1538-7445.AM2014-2715