Abstract 4837: Design, Synthesis, and Biological Evaluation of Thieno[2,3-D] and Thieno[3,2-D]pyrimidines As Dual Acting RTK Inhibitors and Microtubule Targeting Antitumor Agents

Abstract Microtubules, attractive targets for drug development as anticancer agents, play vital roles in multiple aspects of cellular metabolism. These agents have been successfully used in the clinic for the treatment of various cancers. However, the utility of such agents are often limited by the emergence of tumor resistance due to overexpression of P-glycoprotein and/or âIII-tubulin. Tumor angiogenic mechanisms are important for tumor growth and metastasis are inhibited by antiangiogenic agents (AAs). AAs are usually cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of antiangiogenic agents with antitubulin agents have been particularly successful. Recently, we reported water-soluble tubulin targeting pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidine analogs as antitumor agents, that circumvent drug resistance. These analogs also possess RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. To further explore the activity of these dual RTK/tubulin inhibitors we designed isosteric thieno[2,3-d] pyrimidine and thieno[3,2-d]pyrimidine analogs which increased microtubule depolymerizing potency by 14 to 24-fold (AG95 IC50 = 7.0 ± 2.7 nM, AG370 IC50 = 7.6 ± 2.1 nM) compared with the lead compounds (AG85 IC50 = 96.6 ± 5.3 nM, AG20 IC50 = 183 ± 3.4 nM). Substitution at the 4-anilino position of both these scaffolds were also explored with various moieties to afford the 6-methoxy-tetrahydroquinoline moiety which possess the optimum balance of microtubule depolymerizing activity (AG372 IC50 = 4.3 ± 1.6 nM, AG337 IC50 = 3.4 ± 0.9 nM,) and RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. These two compounds demonstrated excellent inhibition for EGFR (IC50 = 12.6 ± 1.2 nM, 28.5 ± 3.9 nM), VEGFR-2 (25.2 ± 7.2 nM, 216.1 ± 18.6 nM) and PDGFRâ (IC50 = 25.6 ± 7.2 nM, 266.8 ± 35.4 nM) comparable to the standard clinically used agents. These attributes of the 4-N-substituted thieno pyrimidines provides the impetus for further development of these compounds as dual acting targeted antitumor agents. Citation Format: Aleem Gangjee, Farhana Islam, Tasdique Mohammad Quadery, Susan L. Mooberry, Anja Bastian, Michael A. Ihnat. Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4837.