c-Myc is an oncogenic transcriptional factor, which form a dimer with Max to activate its transcription activity, driving tumor initiation, progression and poor prognosis in 80% of all tumor types. IGH/Myc genomic translocations have been identified in B-cell lymphoma (15-100%). The amplification of Myc family members, MYC, MYCN, or MYCL have been revealed in 20% patients with small cell lung cancers (SCLC). Therefore It is highly warranted to discover and develop novel c-Myc inhibitors targeting c-Myc dependent tumors (Lymphoma and SCLC) with acceptable therapeutic index. Here we described the discovery of GT19077, a c-Myc/Max PPI small molecule inhibitor, and GT19506, a c-Myc PROTAC, for targeting Myc-dependent tumors. GT-19077 was demonstrated to disrupt c-Myc/Max dimer with an IC50 of 1.0 µM in PPI assays and degraded c-Myc protein with IC50 of 0.34 µM in HL-60 cells measured in c-Myc ELISA assays, which was confirmed by Western Blotting (WB). GT19506 (PROTAC) effectively degraded c-Myc proteins in HL-60 cells with an IC50 of 0.10 µM. The selectivity of both compounds against the physiologic function of c-Myc was determined in growth factor-stimulated hematopoietic progenitor cells by using c-Myc ELISA assays. GT19077 and GT19506 were less potent at degrading c-Myc in growth-factor driven hematopoietic cells with IC50 of 2.36 and 2.40 µM respectively, suggesting a 6-fold and 24-fold selectivity, respectively, which was further confirmed by WB. Further, GT19077 and GT19506 were evaluated in panels of blood cancer and SCLC cell lines carrying Myc genetic alterations, as measured by. GT19077 was shown to selectively inhibit the proliferation of B-cell malignant cells with IGH/Myc genomic translocations in a panel of 14 blood cancer cell lines tested by CellTiter-Glo® Luminescent Cell Viability Assays (CTG). Consistently, GT19506 also selectively inhibited the proliferation of B-cell malignant cells in the panel of 28 blood cancer cell lines tested. Both compounds also inhibited the proliferation of SCLC cells in a panel of 18 SCLC cell lines tested (66% and 22%, respectively). Moreover, GT19077 inhibited c-Myc-driven tumor biology, including G2/M arrest and CD-47 and PD-L1 down-regulation. Finally, GT19077 and GT19506 demonstrated PK dependent c-Myc target engagement in HL-60 and Ramos xenograft tumor models. In conclusion, GT19077 and GT19506 are currently in Lead Optimization Phase, which demonstrate the desired selectivity of targeting Myc dependent B-cell malignancies and Myc-amplified SCLC, but sparing c-Myc in growth factor/cytokine regulated blood progenitor cells. The defined selectivity has enabled the ongoing in vivo efficacy studies, currently GT19077 and GT19506 have being evaluated in in vivo efficacy studies.
Citation Format: Liandong Ma, Youzhi Tong, Qianxiang Zhou, Zhaohui Yang, Honghau Yan, Ye Chen, Ruo Xu, Jie Pan, Xiaoqi Gou, Weidong Qian, Jie Chen, Qi Sun, Luhua Lai. Discovery of GT19077, a c-Myc/Max protein-protein Interaction (PPI) small molecule inhibitor, and GT19506 a c-Myc PROTAC molecule, for targeting c-Myc-driven blood cancers and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1265.