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1547 Discovery of GT19077, a c-Myc/Max Protein-Protein Interaction (PPI) Small Molecule Inhibitor, for Targeting c-Myc-Driven Blood Cancers

Program: Oral and Poster Abstracts
Session: 802. Chemical Biology and Experimental Therapeutics: Poster I
Hematology Disease Topics & Pathways:
apoptosis, Non-Biological, cell division, Animal models, Therapies, cell regulation, Biological Processes, white blood cells, Technology and Procedures, Cell Lineage, Xenograft models, Study Population, genetic profiling, pharmacology, hematopoiesis, flow cytometry, molecular interactions, pathways, signal transduction
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Liandong Ma, MD1*, Youzhi Tong, PhD2*, Zhaohui Yang, PhD2*, Qianxiang Zhou, PhD2*, Honghua Yan, PhD2*, Ye Chen2*, Jie Chen, PhD2*, Honglei Bi2*, Jie Pan2*, Cui Wang2*, Rou Xu, PhD2*, Qi Sun, PhD3* and Luhau Lai, PhD3*

1R&D, Kintor Pharmaceutical Limited, Suzhou, China
2Kintor Pharmaceutical Limited, Suzhou, China
3Peking University, Beijing, China

c-Myc is an oncogenic transcriptional factor, which plays important roles in tumor initiation, progression and poor prognosis in 80% of all tumor types. IGH/Myc genomic translocations have been identified in 100% Burkitt Lymphoma (BL) and 10-15% of other Non-Hodgkin lymphoma (NHL) including Diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL) as well as B-cell multiple myeloma (MM) and myeloid malignancies (AML) with c-Myc genetic alterations. c-Myc genomic alterations and dysregulation have been directly linked to the poor clinical outcome in these blood cancers, which make c-Myc an attractive target for pharmacological inhibition as an urgent unmet medical need. However, c-Myc has been considered as “an undruggable” target since it is an intrinsically disordered protein and tightly regulates key physiological functions under normal conditions. Therefore, novel c-Myc inhibitors with selectivity of targeting c-Myc dependent NHL, MM and acceptable therapeutic index are highly warranted.

c-Myc dimerizes with Max to activate its oncogenic transcription activity. Here we described a c-Myc/Max PPI small molecule inhibitor GT-19077, which disrupted c-Myc/Max dimer with an IC50 of 1.0 µM in PPI assays and inhibited c-Myc transcription activity in reporter assays with an IC50 of 0.50 µM . The disruption of c-Myc/Max complex induced c-Myc instability and degradation with IC50 of 0.34 µM in c-Myc-dependent HL-60 AML cells measured by ELISA assays. The effective degradation of c-Myc was then confirmed in both HL-60 and Ramos (BL) cells by Western Blotting (WB). In contrast, GT19077 was six-fold less potent for c-Myc degradation in GM-CSF-stimulated TF-1 erythroid progenitor cells with an IC50 of 2.31 µM, which was defined as a 6-fold selectivity and considered as a criterion for in vivo tolerability studies. GT19077 was also much less active at degrading c-Myc in GM-CSF-stimulated TF-1 or IL-2-stimulated lymphoid progenitor NK-92 cells assayed by WB. Dysregulated c-Myc is one of major oncogene drivers in B-cell lymphoma, MM and AML. Therefore, GT19077 was evaluated in a panel of 14 hematologic malignant cell lines expressing dysregulated c-Myc or other oncogene drivers. The results showed that GT19077 selectively inhibited the proliferation of all seven B-cell malignant cell lines tested, carrying IGH/Myc translocations (6/7) or Kras G12A mutation (1/7), with IC50s as low as 160 nM. In addition, two myeloblast cell lines and one monoblast cell line were also sensitive to GT19077 with IC50 of 300-700 nM. In contrast, GT19077 showed almost no effect on the proliferation of the rest of three leukemia cell lines carrying other oncogene drivers, including JAK2V617F in HEL cells, AML-ETO in Kasumi-1 cells and FGFR fusion in KG-1 cells. These results suggest GT19077 effectively inhibits c-Myc-dependent blood cancers, but has less effect on the blood cancer cells expressing other oncogene drivers. Moreover, GT19077 inhibited c-Myc-driven tumor biology, which included inducing cell cycle arrest at G2/M and down-regulating immune oncology targets CD-47 and PD-L1 in c-Myc-dependent HL-60 cells. Furthermore, GT19077 demonstrated a favorable PK profile in vivo and degraded c-Myc proteins in HL-60 and Ramos xenograft tumor models.

In conclusion, GT19077 is a potent c-Myc/Max PPI inhibitor Lead molecule with the desired selectivity of targeting c-Myc in c-Myc dysregulated blood cancers, but sparing c-Myc in growth factor/cytokine regulated blood progenitor cells. Importantly, GT19077 effectively inhibits the proliferation of B-cell lymphoma, MM and AML cells carrying c-Myc genetic alterations, including IGH/Myc translocations, but lacks activity in blood cancer cells expressing other oncogene drivers. These results can help develop biomarkers for patient tailoring strategy. Finally, GT19077 demonstrates PK-dependent target engagement in vivo and is currently being evaluated in in vivo efficacy studies.

Disclosures: Ma: Kintor Pharmaceutical Limited: Current Employment, Current equity holder in publicly-traded company. Tong: Kintor Pharmaceutical Limited: Current Employment, Current equity holder in publicly-traded company. Yang: Kintor Pharmaceutical Limited: Current Employment. Zhou: Kintor Pharmaceutical Limited: Current Employment. Yan: Kintor Pharmaceutical Limited: Current Employment. Chen: Kintor Pharmaceutical Limited: Current Employment. Chen: Kintor Pharmaceutical Limited: Current Employment. Bi: Kintor Pharmaceutical Limited: Current Employment. Pan: Kintor Pharmaceutical Limited: Current Employment. Wang: Kintor Pharmaceutical Limited: Current Employment. Xu: Kintor Pharmaceutical Limited: Current Employment.

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