China-based Kintor Pharmaceutical Ltd (HKG: 9939) has published positive results from a pre-clinical study of its dual c-Myc/GSPT1 degrader GT19715 in acute myeloid leukemia (AML) and lymphomas. The findings highlight the potential of GT19715 as a targeted therapy for these challenging cancers.
Pre-Clinical Study Results
Cell-free, cellular assays, and animal studies demonstrated that GT19630/GT19715 (GT19715, the salt form of GT19630) effectively degraded the oncogenic c-Myc protein (IC50 = 1.5 nM) in HL-60 cells. The IC50 of GT19715 in HL-60 cells was 1.8 nM, significantly lower than the 40.2 nM IC50 of normal myeloid progenitors in CFU assay, suggesting a therapeutic window. GT19630 shares chemical properties with other CELMoDs, and proteomic analyses revealed degradation of translation termination factor G1 to S phase transition proteins 1 (GSPT1), an important factor in leukemia stem cell (LSC) survival. GT19715 eliminated circulating blasts and prolonged survival in the c-Myc-driven systemic Daudi leukemia/lymphoma model. Importantly, GT19715 induced cell killing independent of TP53 status.
Significance of c-Myc Targeting
The oncoprotein c-Myc governs the epigenome and transcriptome and is deregulated in 70% of all human cancers. MYC is highly expressed in TP53 mutant or venetoclax-resistant AML. Despite its critical role, targeting c-Myc or the MYC pathway has proven challenging. PROTACs (proteolysis targeting chimeras) and cereblon E3 ligase modulators (CELMoDs) represent attractive modalities for specifically targeting previously undruggable oncoproteins.
Future Outlook
The positive pre-clinical results for GT19715 underscore Kintor Pharmaceutical’s commitment to advancing innovative cancer therapies. By targeting c-Myc and GSPT1, GT19715 has the potential to address significant unmet medical needs in AML and lymphomas.-Fineline Info & Tech
