Selective Targeting of c-Myc-Dependent B-Cell and Myeloid Malignancies by GT19077, a Novel PPI Inhibitor

The abstract highlights the discovery and development of a small molecule inhibitor, GT-19077, which targets the protein-protein interaction (PPI) of c-Myc/Max, a significant oncogene driver in various tumor types. c-Myc has been challenging to target due to its intrinsically disordered nature and its role in normal cell functions, leading to its reputation as "undruggable." However, GT-19077 has shown selectivity in degrading c-Myc and inhibiting the proliferation of c-Myc-addictive B-cell and myeloid malignant cells while sparing JAK2-STAT5 dependent erythroblast cells.

The identification of GT-19077 involved conformation prediction, virtual screening of over 200,000 molecules, and experimental validation. The inhibitor demonstrated direct binding activity to c-Myc in HL-60 myeloid leukemia cells, as evidenced by Cellular Thermal Shift Assay (CETSA). It selectively degraded c-Myc in HL-60 cells with a significantly lower DC50 compared to TF-1 erythroblast cells and inhibited their proliferation selectively.

GT-19077 was further profiled against a panel of 14 hematologic malignant cell lines with c-Myc overexpression. It selectively inhibited the proliferation of all seven B-cell malignant cell lines tested, including those with Myc-IGH translocations and Kras G12A mutations. Additionally, it showed sensitivity against two myeloblast and one monoblast cell line, but had minimal effects on leukemia cell lines driven by different oncogenes.

The inhibitor displayed a favorable pharmacokinetic profile, with a bioavailability of 57.3% in rats upon intraperitoneal administration and is currently under evaluation in animal models for B-cell and myeloid malignancies. The unique selectivity and potency profile of GT-19077 suggest its potential in developing therapies for c-Myc-addictive B-cell and myeloid malignancies, offering a promising avenue for treating these cancers.