Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC. It has also been reported that PRKACA kinase activity is essential for its oncogenic activity, suggesting that PRKACA kinase inhibition could be considered as an useful therapeutic target. In this study, we established an evaluation system for PRKACA kinase inhibitors and synthesized DS89002333, a novel PRKACA inhibitor. DS89002333 showed potent PRKACA inhibitory activity and inhibited fusion protein-dependent cell growth both in vitro and in vivo. Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.

Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.

Discovery of novel chiral diazepines as bombesin receptor subtype-3 (BRS-3) agonists with low brain penetration.

The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.

Arylpiperazines as fatty acid transport protein 1 (FATP1) inhibitors with improved potency and pharmacokinetic properties.

The discovery and optimization of a novel series of FATP1 inhibitors are described. Through the derivatization process, arylpiperazine derivatives 5k and 12a were identified as possessing potent in vitro activity against human and mouse FATP1s as well as excellent pharmacokinetic properties. In vivo evaluation of triglyceride accumulation in the liver, white gastrocnemius muscle and soleus is also described.

Discovery and optimization of novel fatty acid transport protein 1 (FATP1) inhibitors.

The discovery, optimization and structure-activity relationship of novel FATP1 inhibitors have been described. The detailed SAR studies of each moiety of the inhibitors combined with metabolite analysis led to the identification of the potent inhibitors 11p and 11q with improved blood stability.