Part I. Synthesis and biological evaluation of 5HT2B antagonists for liver fibrosis Part II. Identification of new KDM5B inhibitors for colorectal cancer

Abstract

This work has been divided into two major parts. Part I. Synthesis and biological evaluation of 5HT2B antagonists for liver fibrosis Part II. Identification of new KDM5B inhibitors for colorectal cancer Part I. Synthesis and biological evaluation of 5HT2B antagonists for liver fibrosis Liver fibrosis is characterized by excessive accumulation of extracellular matrix components, leading to the distortion of liver architecture and function. This condition poses serious health risks by impairing the ability of the liver to detoxify and metabolize substances and can be a precursor to severe liver diseases such as cirrhosis and hepatocellular carcinoma. Notably, recent studies have shown that the expression of the 5-hydroxytryptamine receptor 2B (5HT2B) is induced during the activation of hepatic stellate cells. Antagonism of 5HT2B stimulates the apoptosis of activated hepatic stellate cells and inhibits their proliferation while concurrently regressing hepatocyte proliferation. These findings underscore the therapeutic potential of targeting 5HT2B in liver fibrosis. In this study, we present compound 19c, which demonstrates promising efficacy both in vitro and in vivo. 19c showed robust in vitro activity with an IC50 value of 1.05 nM and limited blood-brain barrier penetration. Furthermore, 19c did not significantly inhibit hERG and Cytochrome P450 enzymes. 19c markedly reduced fibrotic deposition, with a dose-dependent decrease in fibrosis stage and area in the CCl4-induced liver fibrosis mouse model. Additionally, treatment with 19c led to downregulation of key fibrosis-related genes, including α- SMA, Timp1, Col1a1, and Col3a1, in a dose-dependent manner. Taken together, these results suggest that 19c has the potential to be a novel anti-fibrotic agent. Part II. Identification of new KDM5B inhibitors for colorectal cancer Colorectal cancer (CRC) represents a significant and prevalent cause of cancer-related mortality globally, posing substantial challenges related to therapeutic resistance and metastatic progression. Evidence has identified KDM5B (histone lysine demethylase 5B, also known as JARID1B (Jumonji/AT-rich interactive domain-containing protein 1B)) as a promising therapeutic target for colorectal cancer. Notably, KDM5B expression was significantly elevated in CRC tissues, and its downregulation led to a markable decrease in CRC cell proliferation. Based on these findings, we designed and synthesized a series of arylhydrazone compounds as potential KDM5B inhibitors. Among these, compound 9c exhibited compelling in vitro activity, achieving an IC50 value of less than 1 nM. Furthermore, 9c demonstrated 30% oral bioavailability, and displayed selective cytotoxicity in multiple colorectal cancer cell lines while preserving the viability of normal cells. Compound 9c effectively reduced tumor volume and weight in syngeneic MC38 tumor model, without causing body weight loss.