Hot-Spot Residue-Based Virtual Screening of Novel Selective Estrogen-Receptor Degraders for Breast Cancer Treatment.

The estrogen-receptor alfa (ERα) is considered pivotal for breast cancer treatment. Although selective estrogen-receptor degraders (SERDs) have been developed to induce ERα degradation and antagonism, their agonistic effect on the uterine tissue and poor pharmacokinetic properties limit further application of ERα; thus, discovering novel SERDs is necessary. The ligand preferentially interacts with several key residues of the protein (defined as hot-spot residues). Improving the interaction with hot-spot residues of ERα offers a promising avenue for obtaining novel SERDs. In this study, pharmacophore modeling, molecular mechanics/generalized Born surface area (MM/GBSA), and amino-acid mutation were combined to determine several hot-spot residues. Focusing on the interaction with these hot-spot residues, hit fragments A1-A3 and A9 were virtually screened from two fragment libraries. Finally, these hit fragments were linked to generate compounds B1-B3, and their biological activities were evaluated. Remarkably, compound B1 exhibited potent antitumor activity against MCF-7 cells (IC50 = 4.21 nM), favorable ERα binding affinity (Ki = 14.6 nM), and excellent ERα degradative ability (DC50 = 9.7 nM), which indicated its potential to evolve as a promising SERD for breast cancer treatment.

Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1H)-one derivatives as potent and highly selective FGFR4 inhibitors. Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines. Additionally, A34 demonstrated remarkable antitumor efficacy in a Hep-3B HCC xenograft model, with favorable pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L mutant in vitro, which indicates that it has the potential as a novel anticancer agent for HCC.