Author: Seow-En, Isaac ; Tan, Iain B. ; Shanmugam, Raghuvaran ; Tan, Chris S.H. ; Qi, Ong Y. ; Chong, Dawn Q. ; Macalinao, Dominique C. ; Leow, Wei Q. ; Idzham, Khaireen ; Kong, Yap C. ; Chang, Hong Y. ; Shin, Seung H. ; Shi, Wei ; Chok, Aik Y. ; Murata-Hori, Maki ; Fidan, Kerem ; Xiaoqian, Zhang ; Wee, Ian ; Vaiyapuri, Thamil S. ; Tan, Emile ; Lee, Fiona ; Dasgupta, Ramanuj ; Majee, Prativa ; Shumei, Chia ; Ozturk, Mert B. ; Low, Joo-Leng ; Tergaonkar, Vinay ; Chua, Joelle Y.H. ; Raju, Anandhkumar

AbstractOver-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic.Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.

01 Oct 2024·Molecular Carcinogenesis

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer

Article

Author: Alejo, Salvador ; He, Yi ; Viswanadhapalli, Suryavathi ; Jayamohan, Sridharan ; Zou, Yi ; Sareddy, Gangadhara R. ; Lai, Zhao ; Johnson, Jessica D. ; Venkata, Prabhakar P. ; Jamwal, Diksha ; Vadlamudi, Ratna K. ; Chen, Yihong ; Kost, Edward

AbstractOvarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum‐based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy‐resistant disease. Recent studies have revealed that the epigenetic modifier lysine‐specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient‐derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin‐resistant A2780‐CP70 cells to carboplatin treatment and paclitaxel‐resistant SKOV3‐TR cells to paclitaxel. RNA‐seq analysis revealed that a combination of KDM1A‐KD and cisplatin treatment resulted in the downregulation of genes related to epithelial‐mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF‐κB pathway genes, and KDM1A‐KD or KDM1A inhibition reversed this effect. Importantly, KDM1A‐KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

01 Aug 2024·Immunologic Research

Inhibition of LSD1 via SP2509 attenuated the progression of rheumatoid arthritis

Article

Author: Liu, Wei ; Liu, Lei ; Liu, Jian ; Gao, Dagong ; Yu, Ziliang ; Li, Peipei ; Zhang, Haiping ; Hu, Yalong ; Xia, Fei

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Lysine-specific demethylase 1 (LSD1), an enzyme involved in transcriptional regulation, has an unclear role in synovial inflammation, fibroblast-like synoviocytes migration, and invasion during RA pathogenesis. In this study, we observed increased LSD1 expression in RA synovial tissues and in TNF-α-stimulated MH7A cells. SP2509, an LSD1 antagonist, directly reduced LSD1 expression and reversed the elevated levels of proteins associated with inflammation, apoptosis, proliferation, and autophagy induced by TNF-α. Furthermore, SP2509 inhibited the migratory capacity of MH7A cells, which was enhanced by TNF-α. In CIA models, SP2509 treatment ameliorated RA development, reducing the expression of pro-inflammatory cytokines and alleviating joint pathological symptoms. These findings underscore the significance of LSD1 in RA and propose the therapeutic potential of SP2509.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Preclinical	Singapore	Agency for Science, Technology & Research	17 Jun 2024
Neoplasms	Preclinical	United States	Salarius Pharmaceuticals, Inc.	-

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