LAUSR

Therapeutic inhibition of the MYC oncoprotein action for cancer treatment is a challenging aim and various anti-MYC approaches, including the development of small-molecule candidate drugs, are being actively pursued. Using genetically-modified mouse models of cancer, we have demonstrated that the oncogenicity of mutant KRAS causally depends on unperturbed MYC activity. On the basis of this observation, we performed preclinical studies and treated successfully mouse pancreatic, breast and other cancers, and also xenografts of human pancreatic cancer cell lines, by using Mycro3, an orally-bioavailable small-molecule inhibitor of MYC-MAX dimerization. We observed that, in comparison with vehicle-treated controls, tumor growth in Mycro3-treated mice was drastically attenuated.1 To optimize Mycro3, we have used drug design, organic synthesis, in vitro assays, pharmacokinetic profiling, and in vivo efficacy studies. These efforts led to the identification of novel derivatives, one of which (Amy22) exhibits a vastly improved therapeutic window against MYC (>300-fold over Mycro3). It has also superior physicochemical and pharmacokinetic properties (the peak blood concentration is >6-fold better over Mycro3, while the compound bioavailability is maintained for more than 12 hours). The designed candidate anti-Myc compounds were synthesized by coupling properly substituted pyrazolo[1,5-a]pyrimidines with various amines, and then evaluated in vitro using the TGR-1 (Myc+/+) and H015.19 (Myc-/-) sibling cell lines. The in vivo efficacy of Amy22 has been tested successfully in preclinical studies using advantageous mouse models of MYC overexpressing tumors that we have developed, which enable rapid evaluations. Moreover, patient-derived xenografts (PDXs) are being used, while combinatorial therapeutic regimes using anti-Myc treatment with drugs inhibiting other collaborating tumorigenic pathways have been evaluated.2 ZC has been co-funded by the European Commission under the H2020 Research Infrastructures Contract No. 675121 (project VI-SEEM). 1D. Stellas, M. Szabolcs, S. Koul, Z. Li, A. Polyzos, C. Anagnostopoulos, Z. Cournia, C. Tamvakopoulos, A. Klinakis & A. Efstratiadis (2014) Therapeutic Effects of an anti-Myc Drug on Mouse Pancreatic Cancer, J Natl Cancer Inst, 106(12). pii: dju320 2D. Stellas, Z. Cournia, C. Tamvakopoulos, A. Klinakis & A. Efstratiadis. “Novel Compounds for use in treating or preventing cancerous diseases”. International Patent Application number PCT/EP2016/066340 Citation Format: Veroniki P. Vidali, Zoe Cournia, Adriana Papadimitropoulou, Dimitrios Stellas, Apostolos Klinakis, Elias A. Couladouros, Constantin Tamvakopoulos, Argiris Efstratiadis. Design, synthesis, and efficacy of MYC inhibitors in mouse pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-262.