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199 C-MYC Targeting By Degradation: Novel Dual c-Myc/GSPT1 Degrader GT19715 Induces TP53-Independent Cell Death in Acute Myeloid Leukemia and Lymphomas

Program: Oral and Poster Abstracts
Type: Oral
Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Targeted Protein Degradation and Emerging Small Molecule Inhibitors in Myeloid Neoplasms
Hematology Disease Topics & Pathways:
Research, Translational Research, drug development, Therapies
Saturday, December 10, 2022: 2:00 PM

Yuki Nishida, MD, PhD1, Darah A Scruggs, MS1*, Edward Ayoub, PhD1*, Tallie Patsilevas, BS2*, Vivian Ruvolo, MS2*, Po Yee Mak1*, Bing Z Carter, PhD1, Steffen Boettcher3*, Abhishek Maiti, MBBS2, Qianxiang Zhou, PhD4*, Zhaohui Yang, PhD4*, Honghua Yan, PhD4*, Liandong Ma, MD4 and Michael Andreeff, MD, PhD1

1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Medical Oncology and Hematology, University of Zurich and University Hospital of Zurich, Zurich, Switzerland
4Kintor Pharmaceutical Limited, Suzhou, China

The oncoprotein c-Myc, a major regulator of the epigenome and transcriptome is dysregulated in 70% of all human cancers. MYC is highly expressed in Burkitt’s leukemia/lymphomas and also in TP53 mutant and venetoclax (ven) resistant AML (Sallman, Blood 2021, Nishida, ASH 2021). However, targeting c-Myc or the MYC pathway has not been successful and remains a major unmet clinical need. We here report the first c-Myc degrading agent in pre-clinical development. Cerebron E3 ligase modulators (CELMoDs) is an emerging treatment modality to target hitherto undruggable oncoproteins. We developed the first c-Myc degrader GT19630 (GT19715 is the salt form of GT19630). C-Myc was pulled down by biotinylated GT19630 in a cell-free, in vitro affinity purification assay and was degraded withIC50 of 1.5 nM in HL-60 cells. A proteasome inhibitor ixazomib completely blocked c-Myc degradation, confirming CRL4CRBN-dependent c-Myc degradation as mechanism. IC50 of GT19715 in HL-60 cells was 0.33 nM, considerably lower than the IC50 of 44.9 nM and 42.9 nM in normal erythroid and myeloid progenitors CFU assays, suggesting a therapeutic window. In agreement with other CELMoDs, proteomic analyses revealed degradation of translation termination factor GSPT1 (G1 to S phase transition proteins 1), an important factor in LSC survival (Surka et al. Blood 2021), suggesting a dual activity of GT19630 against c-Myc and GSPT1. Whereas a selective GSPT1 degrader CC-90009 reduced GSPT1 protein levels but not c-Myc, GT19715 reduced both c-Myc and GSPT1 (Fig. A) and exerted a 20x higher cytoreductive potency compared to CC-90009 (IC50 of 1.8 nM vs 40.4 nM for GT19715 and CC-90009, respectively) in HL-60 cells. GT19630 degraded c-Myc and GSPT1 in a xenograft model with HL-60 cells, and inhibited tumor growth at a dose as low as 0.3 mg/kg/bid. GT19630 had no effect on normal myeloid lineages in rats at 6 mg/kg. As expected, GT19715 eliminated circulating blasts and prolonged survival in the c-Myc-driven systemic Burkitt’s leukemia/lymphoma model (Daudi) (Fig. B). GT19715 significantly reduced human CD45+ AML blasts in peripheral blood, bone marrow and spleens compared to vehicle controls in vivo in a chemotherapy-resistant AML PDX model . Importantly, GT19715 induced cell death independent of TP53 status. Baseline c-Myc protein levels significantly correlated with sensitivity to GT19715 in MOLM-13 cells with CRISPR engineered knockout/mutations of TP53 (R2 = 0.86, P = 0.02). Indeed, GT19715 induced comparable cell death in primary AML samples with wild-type or mutant TP53 (62.6% and 61.6% annexin V/DAPI positivity, P = 0.65 for wild-type and mutant TP53 samples at 64 nM of GT19715, respectively). CD34+ AML cells were more susceptible to GT19715 than CD34- AML cells, suggesting a greater efficacy in AML stem/progenitor than in more mature AML cells. Chromatin-enriched proteomics confirmed c-Myc as one of the most significantly downregulated proteins; and identified ERF1, a binding partner of GSPT1 that promotes translation termination, as one of the top upregulated proteins, implicating a compensatory response against GSPT1 degradation. Finally, we found that MV4;11 ven resistant (VR) cells generated through long-term ven exposure demonstrated elevated protein levels of c-Myc and GSPT1 and exhibited greater sensitivity to GT19715 compared to ven-sensitive parental cells. CK1α, another target protein of thalidomide derivatives, was not degraded by GT19715 in MV4;11 parental and VR cells with no induction of p53, supporting p53-independent cell death. Conclusions: The novel dual c-Myc/GSPT1 degrader GT19715 exerts TP53 independent preclinical anti-lymphoma and -leukemia efficacy, providing rationale for its clinical development.

Disclosures: Nishida: Daiichi-Sankyo Inc.: Research Funding; Kintor Pharmaceutical: Research Funding. Carter: PinotBio: Research Funding; Syndax: Research Funding; Revolution Medicines: Research Funding. Zhou: Kintor Pharmaceutical: Current Employment. Yang: Kintor Pharmaceutical: Current Employment. Yan: Kintor Pharmaceutical: Current Employment. Ma: Kintor Pharmaceutical: Current Employment. Andreeff: Syndax: Consultancy, Research Funding; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Reata: Current holder of stock options in a privately-held company; Brooklyn ITX: Research Funding; Glycomimetics: Consultancy; Chimerix: Current holder of stock options in a privately-held company; Senti Bio: Consultancy, Research Funding; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo Inc.: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; Medicxi: Consultancy; Oxford Biomedical UK: Research Funding; Pinot Bio: Research Funding; Oncolyze: Current holder of stock options in a privately-held company; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI: Membership on an entity's Board of Directors or advisory committees; Kintor Pharmaceutical: Research Funding.

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