Myc family members (MYC, MYCN and MYCL) are oncogenic transcriptional factors, which form dimers with Max to activate transcription activities to drive tumor initiation and progression. c-Myc deregulation has been identified in 80% of all tumor types, including B-cell malignancies, AML and a variety of solid tumors. N-Myc genetic alterations have been identified in small cell lung cancer, neuroblastoma, neuroendocrine prostate cancers and sarcoma. Myc-deregulation has been directly linked to the poor clinical outcome in these cancers, which makes Myc a therapeutic target for pharmacological inhibition. Here we described GT19630, a c-Myc/n-Myc degrader. GT19630 selectively degraded c-Myc proteins in c-Myc dependent blood cancer cells (IC50=1.5 nM) as compared to growth-factor regulated c-Myc in hematopoietic progenitor cells (TF-1) (IC50=52.5 nM). Similar selectivity of GT19630 has been demonstrated in cell proliferation and granulocyte–macrophage progenitor colony forming unit (GM-CFU) assays with the IC50s of 26.2 and 39.0 nM, respectively. GT19630 was shown to degrade c-Myc via proteasome degradation system and degraded CRBN-dependent endogenous neo-substrates of GSPT1, CK1α and IKZF1. GT19630 reduced transcriptional factors including c-Myc, Max, MXI1, SWF/SNF family members/associated proteins; ARID1A, SMARCE1, and SMARCC1 in transcriptional factor response element (TFRE) assays. Moreover, GT19630 inhibited the cell proliferation with IC50<10 nM in 74% of B-cell malignant cell lines (20/27) bearing deregulated c-Myc. Importantly, GT19630 was demonstrated to degrade Myc proteins completely and induced tumor regression or tumor eradication in AML, lymphoma and multiple myeloma (MM) animal xenograft tumor at lowest dose of 0.3 mpk/qd. In addition, GT19630 demonstrated an even-driven pharmacology in vivo and induced complete AML tumor regression with an intermittent dosing regimen of 3d on/7d off. Furthermore, GT19630 degraded n-Myc in SCLC, and neuroblastoma cells and demonstrated target-engaged efficacy in SCLC tumor models. Finally, GT19630 demonstrated favorable PK and safety profiles in rat after Rx for 14 days. In conclusion, GT19630 is a potent c-Myc/n-Myc degrader, which induced complete tumor regression and eradicated lymphoma cells in c-Myc/n-Myc dependent animal models (lymphoma, MM and AML and SCLC) without heme toxicity in vivo. GT19630 has achieved favorable PK profile and therapeutic index, which help advance this compound to IND-enabling stage.
Citation Format: Liandong Ma, Yuzhi Tong, Zhaohui Yang, Qianxiang Zhou, Honghua Yan, Ye Chen, Dong Chen, Ru Xu, Yini Wang, Jun Qin. Discovery and evaluation of GT19630, a c-Myc/n-Myc degrader, for targeting c-Myc-driven B-cell malignancies, acute myeloid leukemia (AML) and n-Myc driven cancers [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A03.