Abstract 3929: Identification of MRT-2359 a potent, selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) for the treatment of cancers with Myc-induced translational addiction

Abstract

Abstract Myc transcription factors are well-established drivers of human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy targeting the Myc family members directly has been developed to date. To sustain uncontrolled cell proliferation and tumor growth, Myc-driven cancers are known to be addicted to protein translation. This addiction creates a dependency on critical components of the translational machinery providing in turn a unique opportunity for therapeutic intervention. We hypothesized that targeting the translational termination factor GSPT1, a key regulator of protein synthesis, would constitute a vulnerability for Myc-driven tumors. GSPT1 contains a well-defined degron allowing for the recruitment of the E3 ligase cereblon (CRBN) and subsequent proteasomal degradation in the presence of molecular glue degraders. Herein we describe a novel orally bioavailable GSPT1-directed small molecule degrader MRT-2359, which has been rationally designed and optimized to selectively induce apoptosis in translationally addicted cells. MRT-2359 promotes complex formation between CRBN and GSPT1 and potently induces GSPT1 degradation in a CRBN- and degron-dependent manner. The high selectivity of MRT-2359 was subsequently demonstrated by the lack of activity in cells expressing a non-degradable GSPT1 mutant. Although MRT-2359 degrades GSPT1 in all the cell lines tested, profiling in a large panel of cancer lines revealed profound and preferential antiproliferative activity in Myc-driven cell lines, such as high N-Myc expressing non-small cell lung cancer (NSCLC) lines and high L-Myc expressing small cell lung cancer (SCLC) lines. In the Myc-driven cells, degradation of GSPT1 led to translational repression as manifested by a global shift from polysomes to monosomes resulting in the reduction of a subset of proteins as assessed by quantitative proteomics. In particular, N- or L-Myc protein levels decreased and as a consequence the known Myc target genes were downregulated at the mRNA level. Despite the robust degradation of GSPT1, no marked effect was observed in low N-Myc lines, confirming the selective activity of our GSPT1 degrader in Myc-driven lung cancers. Finally, oral administration of MRT-2359 in high N-Myc NSCLC xenografts and PDXs led to complete intratumoral GSPT1 degradation and concomitant decrease in N-Myc protein levels, resulting in tumor regression. In contrast, MRT-2359 had limited or no activity in low N-Myc NSCLC models, further corroborating the selective vulnerability of Myc-driven tumors to GSPT1 degradation. Together these data support the therapeutic potential of GSPT1-directed MGDs in Myc-driven solid tumors addicted to the protein translation machinery and warrant rapid evaluation towards the clinic. Citation Format: Gerald Gavory, Mahmoud Ghandi, Anne-Cecile d’Alessandro, Debora Bonenfant, Agustin Chicas, Frederic Delobel, Brad Demarco, Alexander Flohr, Christopher King, Anne-Laure Laine, Vittoria Massafra, Rajiv Narayan, Arnaud Osmont, Giorgio Ottaviani, Dave Peck, Sarah Pessa, Nooreen Rubin, Thomas Ryckmans, Martin Schillo, Ambika Singh, Simone Tortoioli, Dominico Vigil, Vladislav Zarayskiy, John Castle, Filip Janku, Owen Wallace, Silvia Buonamici, Bernhard Fasching. Identification of MRT-2359 a potent, selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) for the treatment of cancers with Myc-induced translational addiction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3929.