Small cell lung cancer (SCLC) accounts for about 14% of all lung cancer cases. Besides,one of the key regulators of SCLC was identified as lysine-specific demethylase 1A (LSD1 or KDM1A). Specifically, LSD1 plays an integral role in the regulation of gene expression by removing methyl groups from specific lysine residues on histones. Besides, This process can significantly influence the behavior of cells, including their ability to divide and grow uncontrollably, as seen in cancer. In addition, LSD1 also affects the anti-tumor immune response. Noticeably, Bomedemstat (IMG-7289), an orally active and irreversible LSD1 inhibitor that increases methylation at H3K4 and H3K9, thereby altering chromatin structure and subsequently gene expression. Ultimately, Bomedemstat affects SCLC tumor growth and reduces the immunosuppressive environment of SCLC, including improved antigen presentation through upregulation of MHC-I.
Bomedemstat, a LSD1 inhibitor, is an anticancer agent against SCLC
In vitro, Bomedemstat shows remarkable anti-cancer activities. It inhibits cancer cell proliferation, a defining feature of tumors, and induces apoptosis – programmed cell death. Specifically, Bomedemstat selectively inhibits proliferation and induces apoptosis of Jak2V617F cells by concomitantly increasing expression and methylation of p53. Meanwhile, Bomedemstat (50 nM-1 μM; 96 h) enhances survival, induces apoptosis via BCL-XL and PUMA in a TP53-dependent manner, and leads to cell cycle arrest.
In preclinical animal models, Bomedemstat shines bright. It (oral, 45 mg/kg, once daily for 56 days) normalizes or improves blood cell counts and reduces spleen volumes. Moreover, Bomedemstat restores normal splenic architecture and reduces bone marrow fibrosis, underscoring its potential in mitigating the systemic impact of diseases like cancer.
In conclusion, Bomedemstat is an orally active and irreversible LSD1 inhibitor and has potent anticancer activity. As we press ahead on this quest, fueled by science and perseverance, promising therapies like Bomedemstat make the journey worthwhile.
References:
[1] Jonas S Jutzi, et al. Hemasphere.2018 Jun 8;2(3):e54.
[2] Yuan Fang, et al. J Hematol Oncol. 2019 Dec 4;12(1):129.
[3] Sattler M, et al. Transl Lung Cancer Res. 2023 Jun 30;12(6):1350-1354.