PF-06687859 / Pfizer - LARVOL DELTA

Novel Differentially Expressed LncRNAs Regulate Artemisinin Biosynthesis in Artemisia annua. (PubMed, Life (Basel)) - "Three potential lncRNAs (MSTRG.33718.2, MSTRG.30396.1 and MSTRG.2697.4) linked to the key artemisinin biosynthetic genes (ADS: Amorpha-4,11-diene synthase, DXS: 1-deoxy-D-xylulose-5-phosphate synthase, and HMGS: 3-hydroxyl-3-methyglutaryl CoA synthase) were detected...By identifying and characterizing lncRNAs that are potentially linked to the regulation of key biosynthetic genes, this work provides new insights into the complex regulatory networks governing artemisinin production in A. annua. Such findings could pave the way for innovative approaches in metabolic engineering, potentially enhancing artemisinin yields and addressing challenges in sustainable production."

Journal • Infectious Disease

Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma. (PubMed, J Transl Med) - "DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • STAT5B

Involvements of decapping scavenger enzyme DcpS in the progression of glioblastoma (Neuroscience 2023) - "Thus, we focused on RG3039, an decapping scavenger enzyme (DcpS) inhibitor, which can penetrate the blood-brain barrier and be used orally...N-cadherin is one of the major intercellular adhesion molecules and is known to induce interactions such as proliferation and differentiation in various cancer cells. Taken together, these results suggested that DcpS contributes to GBM progression through the expression of N-cadherin, and DcpS selective inhibitors are expected to be a novel treatment for GBM."

CNS Disorders • CCNB1 • CCND1 • CDH2

Ferroptosis induced by DCPS depletion diminishes hepatic metastasis in uveal melanoma. (PubMed, Biochem Pharmacol) - "We found that inhibition of DCPS by shRNA or RG3039 induced gene transcript alteration and ferroptosis through reducing the mRNA turnover of GLRX...Furthermore, targeting DCPS diminished hepatic metastasis of UM cells. These findings may shed light on the understanding of DCPS-mediated pre-mRNA metabolic pathway in UM by which disseminated cells gain enhanced malignant features to promote hepatic metastasis, providing a rational target for metastatic colonization in UM."

Journal • Eye Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GLRX

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC. (PubMed, ACS Chem Biol) - "JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders."

Journal • Acute Myelogenous Leukemia • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

Exploration of novel therapeutic targets in acute myeloid leukemia via genome-wide CRISPR screening (PubMed, Rinsho Ketsueki) - "Importantly, RG3039 exhibited anti-leukemia effects in PDX models. These findings identify DCPS as a novel therapeutic target for AML, shedding new light on the nuclear RNA metabolic pathway in leukemogenesis."

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