Research progress of dual inhibitors targeting crosstalk between histone epigenetic modulators for cancer therapy.

Abnormal epigenetics is a critical hallmark of human cancers. Anticancer drug discovery directed at histone epigenetic modulators has gained impressive advances with six drugs available for cancer therapy and numerous other candidates undergoing clinical trials. However, limited therapeutic profile, drug resistance, narrow safety margin, and dose-limiting toxicities pose intractable challenges for their clinical utility. Because histone epigenetic modulators undergo intricate crosstalk and act cooperatively to shape an aberrant epigenetic profile, co-targeting histone epigenetic modulators with a different mechanism of action has rapidly emerged as an attractive strategy to overcome the limitations faced by the single-target epigenetic inhibitors. In this review, we summarize in detail the crosstalk of histone epigenetic modulators in regulating gene transcription and the progress of dual epigenetic inhibitors targeting this crosstalk.

Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer.

LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent antiproliferative activities against MGC-803 and HCT-116 cancer cell lines. Notably, compound 5m showed superior in vitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP-2509 with IC50 values ranging from 0.23 to 1.56 µM. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced apoptosis, reduced colony formation and suppressed migration in MGC-803 cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.

Serum chitinase-3-like protein 1 is a biomarker of liver fibrosis in patients with chronic hepatitis B in China.

BACKGROUND: Serum chitinase-3-like protein 1 (CHI3L1) is a potential biomarker for fibrosis assessment. We aimed to evaluate serum CHI3L1 as a noninvasive diagnostic marker for chronic hepatitis B virus-related fibrosis. METHODS: Serum CHI3L1 levels were measured by ELISA in 134 chronic hepatitis B (CHB) patients. Significant fibrosis was defined as a liver stiffness > 9.7 kPa. The performance of CHI3L1 was assessed and compared to that of other noninvasive tests by receiver operating characteristic (ROC) analysis. RESULTS: Serum CHI3L1 levels were significantly higher in CHB patients with significant hepatic fibrosis (≥ F2, 81.9 ng/mL) than in those without significant hepatic fibrosis (< F2, 56.5 ng/mL) (P < 0.001). In CHB patients, the specificity and sensitivity of CHI3L1 for predicting significant fibrosis were 75.6% and 59.1%, respectively, with a cut-off of 76.0 ng/mL and an area under the ROC curve of 0.728 (95% CI: 0.637-0.820). CONCLUSIONS: Serum CHI3L1 levels could be an effective new serological biomarker for the diagnosis of liver. Moreover, CHI3L1 is feasible in monitoring disease progression.