Improvement of NASH and liver fibrosis through modulation of the gut-liver axis by a novel intestinal FXR agonist.

Farnesoid X receptor (FXR) plays a pivotal role in the regulation of bile acid homeostasis and is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Although FXR agonists effectively alleviate pathological features of NASH, adverse effects such as disturbance of cholesterol homeostasis and occurrence of pruritus remain to be addressed. Here, we identified a novel FXR agonist, ID119031166 (ID166), and explored the pharmacological benefits of ID166 in the treatment of NASH. ID166, a potent and selective non-bile acid FXR agonist, exhibits preferential distribution in the intestine and shows no agonist activity against potential itch receptors including Mas-related G protein-coupled receptor X4 (MRGPRX4). Interestingly, ID166 significantly attenuated total nonalcoholic fatty liver disease (NAFLD) activity and liver fibrosis in a free choice diet-induced NASH hamster model. In addition, ID166 drastically modulated the relative abundance of five gut microbes and reduced the increase in plasma total bile acid levels to normal levels in NASH hamsters. Moreover, long-term treatment with ID166 significantly improved key histological features of NASH and liver fibrosis in a diet-induced NASH mouse model. In the NASH mouse livers, RNA-seq analysis revealed that ID166 reduced the gene expression changes associated with both NASH and liver fibrosis. Notably, ID166 exhibited no substantial effects on scratching behavior and serum IL-31 levels in mice. Our findings suggest that ID166, a novel FXR agonist with improved pharmacological properties, provides a preclinical basis to optimize clinical benefits for NASH drug development.

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Discovery of Novel Dual Adenosine A2A and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents.

New compounds with 1H-pyrazolo [3,4-d]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A2A and A1 receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA2A Ki = 13.3 nM; hA1 Ki = 55 nM) and full antagonism (hA2A IC50 = 136 nM; hA1 IC50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson's disease, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A2A/A1 receptor antagonist, 11o, is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.

Discovery of novel heat shock protein (Hsp90) inhibitors based on luminespib with potent antitumor activity.

A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.

6-Alkylsalicylic acid analogues inhibit in vitro ATPase activity of heat shock protein 90.

The molecular chaperone heat shock protein 90 (Hsp90) is responsible for maintaining the correct folding and stability of many signaling proteins. It is a promising target of cancer therapeutics and several other diseases, including neurodegenerative disease, nerve injuries, inflammation, and infection. In an effort to identify new Hsp90 inhibitors from natural sources using an in vitro ATPase inhibition assay, two 6-alkylsalicylic acid analogues, salaceyin A and B were identified from the culture extract of Streptomyces. Salaceyin A and B exhibited moderate ATPase inhibitory activities with IC(50) values of 68.3 and 65.2 µM, respectively. Binding of salaceyins to human Hsp90α was examined by competition binding experiments with ATP-Sepharose beads. However, the compounds exhibited no degradation activity of Hsp90 client proteins, Her2, c-Raf, or Akt.