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A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound 10e emerged as highly promising. It exhibited potent inhibitory activity with an IC 50 value of 0.8 nM and possessed moderate clogP. Compounds 10e significantly inhibited solid tumor cells proliferation. Additionally, 10e induced apoptosis and arrested the cell cycle. Furthermore, in vivo studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound 10e as a novel LSD1 inhibitor with robust efficacy both in vitro and in vivo, establishing it as a promising lead compound for further anticancer drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is an attractive agent for treatment of cancer. However, the anti-tumor effect of LSD1 inhibitors against diffuse large B-cell lymphoma (DLBCL) and the underlying mechanism are still unclear. Here, we report that KDM1A is overexpressed in human DLBCL tissues and negatively related to overall survival rate of DLBCL patients. ZY0511, a novel and potent LSD1 inhibitor developed by our group, inhibited the proliferation of human DLBCL cells. ZY0511 interacted with LSD1, induced methylation level of histone 3 lysine 4 and histone 3 lysine 9 in DLBCL cells. Mechanistically, transcriptome sequencing results indicated that ZY0511 induced the genes enrichment significantly related to cell cycle, autophagy, and apoptosis signaling pathways. Further study confirmed that ZY0511 blocked cell cycle at G0/G1 phase and expression of CDK4 and cyclin D1. ZY0511 decreased mitochondrial membrane potential and induced apoptosis, which can be reverted by a pan-caspase inhibitor, Z-VAD-FMK. Moreover, ZY0511 treatment significantly increased autophagy-associated marker proteins and autophagosomes formation in DLBCL cells. In vivo xenograft experiments confirmed that intraperitoneal administration of ZY0511 significantly suppressed SU-DHL-6 xenograft tumor growth in vivo. In conclusion, our findings identify that ZY0511 inhibits DLBCL growth both in vitro and in vivo via the induction of apoptosis and autophagy, and LSD1 inhibitor might be a promising strategy for treating DLBCL., (© 2021. The Author(s).)

Human dihydroorotate dehydrogenase ( h DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3- d ][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against h DHODH. Further optimization led to compounds 11k and 11l , which inhibited h DHODH activity with IC 50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with h DHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with h DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.

Lysine-specific demethylase1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the mechanism underlying the role of LSD1 in oncogenesis is poorly understood, and more effective LSD1 inhibitors are needed. Here we report the biological activity of a novel LSD1 inhibitor named ZY0511. ZY0511 specifically inhibited LSD1 activity and the proliferation of various human cancer cells especially the HeLa and HCT116 cells. ZY0511 significantly increased the expression of DDIT4, a known mTORC1 suppressor, which was a direct downstream target of LSD1 confirmed by ChIP-PCR. ZY0511-induced LSD1 inhibition upregulated the expression of DDIT4 by altering histone H3K4 methylation levels at its promoter, thus suppressing mTORC1 activity. Knockdown of DDIT4 attenuated the anticancer effect of ZY0511. Intraperitoneal administration of ZY0511 significantly prevented the growth of HCT116 and HeLa xenografts in mice and showed no detectable toxicity. Moreover, DDIT4 expression was correlated with the sensitivity of human cancer cells to chemotherapy. Taken together, ZY0511 showed therapeutic potential for solid tumors, the induction of DDIT4 may be used as a predictive biomarker of LSD1 inhibitors., (Copyright © 2019 Elsevier B.V. All rights reserved.)