Abstract 3297: Discovery and evaluation of GT19870, a GSPT1/Myc molecular glue drug (MGD) with oral bioavailability for targeting c-Myc and n-Myc-addictive blood cancer and solid tumors

Abstract

Abstract c-Myc and n-Myc are oncogenic transcriptional factors driving tumor initiation, progression and poor prognosis in a variety of blood cancers and solid tumors, such as acute myeloid leukemia (AML), B-cell malignancies, castration resistance prostate cancer (mCRPC), small cell lung cancer and (SCLC) and neuroblastoma. Both c-Myc and n-Myc dysregulations have been directly linked to the poor clinical outcome in some of these cancers which are addictive to deregulated Myc proteins. Therefore, it is highly warranted to discover and develop novel therapeutical agents for targeting Myc-addictive cancers. GT19870 was discovered through a SAR effort for Myc degradation with improved bioavailability (F % 92.52) from GT19630, a GSPT1/Myc degrader series 1-4by using phenotypic screenings with c-Myc-addictive HL-60 AML cells and growth factor-dependent hematopoiesis progenitor TF-1 cells, followed by c-Myc ELISA and Western blot assays. GT19870 selectively inhibited the proliferation of HL60 cells with an IC50 of 2.6 nM as compared to an IC50 of 70.03 nM (26.5-fold selectivity) and effectively degraded c-Myc protein with an IC50 of 2.54 nM and IC90 <10 nM in HL-60 cells, as compared to an IC90>30 nM in CD3/CD28-stimulated PBMC assays. GT19870, as a MGD, was confirmed to selectively degrade GSPT1, a neo-substrate, by proteomic and Western Blot assays. Further, GT19870 was tested in SCLC, triple negative breast cancer (TNBC) and brain cancer cell panels, in which GT1987 was revealed potent anti-proliferation activities with an IC50<50 nM in 9 of 19 SCLC, 8 of 13 TNBC, and 7 of 24 brain cancer cell lines tested. Importantly GT19870 was also shown potent antitumor activities with IC50 of ≦5.4 nM in 8 of 8 SCLC patient derived organoids. Furthermore, GT19870 (salt form-GT19884) was demonstrated to induce target-engaged (c-Myc and n-Myc) tumor regression in AML, SCLC, mCRPC and neuroblastoma xenograft and PDX models with in a dose ranges of 3-12 mpk/qd/po. In brief, GT19870 is an oral MGD degrading GSPT1/c-Myc/n-Myc. This novel MGD has been demonstrated target-engaged antitumor activities in vitro and in vivo with selectivity of c-Myc degradation in c-Myc-addictive cancer cells as compared to growth factor-stimulated TF-1 cells and CD3/CD28 activated PBMC. GT19870 has been progressing IND enabling stage.