Abstract 4857: Design and biological evaluation of substituted pyrrolo[3,2-d]pyrimidines as dual acting RTK and microtubule targeting agents

Abstract

Abstract Combination chemotherapy with antiangiogenic (cytostatic) and microtubule targeting (cytotoxic) agents (MTA) have shown significant promise and several studies with such combinations have progressed to the clinic. Single agents with both antiangiogenic activities as well as cytotoxicity would circumvent pharmacokinetic problems of multiple agents, might be effective at lower doses to alleviate toxicity, and delay or prevent tumor cell resistance. We have designed, synthesized and evaluated single agents that are novel pyrrolo[3,2-d]pyrimidine MTAs that also inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor â (PDGFRâ). Sixteen pyrrolo[3,2-d]pyrimidine analogs were synthesized with variations on the C-2 and the 4-anilino position. The importance of various substituents was evaluated based on their abilities to cause cellular microtubule depolymerization and inhibit proliferation of MDA-MB-435 cancer cells. Compounds with N5-Me were more potent than the N5-H analogs indicating that a conformational restriction induced by N5-Me could mimic the bioactive conformation. In addition, all C2-Cl compounds afforded 2 to 10-fold more potentIC50 values than their C2-Me counterparts as illustrated by C2-Cl analog AG336 (IC50 = 18.3 ± 5.0 nM) compared to its C2-Me analog AG85 (IC50 = 193 ± 39 nM). The most active antitubulin agents were evaluated against RTKs and demonstrated good inhibition for EGFR (IC50 = 29.5 - 91.5 nM), VEGFR-2 (182.3 - 543.6 nM) and PDGFRâ (IC50 = 204.4 - 450.2 nM), thus demonstrating dual-targeting ability. Preclinical assessment of AG165 at 75 mg/kg in mice in the NCI/ADR resistant tumor model demonstrated significant reduction of tumor volume compared to paclitaxel (10 mg/kg) treated mice [p = 0.0333], indicating antitumor activity in a multidrug resistant tumor model, in addition to excellent antitumor activity in MDA-MB-435 and MDA-MB-231 xenograft models. These results demonstrate the viability of these multitargeted single agents as potential clinically active antitumor agents. Citation Format: Aleem Gangjee, Khushbu Shah, Nicholas Dybdal-Hargreaves, Susan Mooberry, Anja Bastian, Michael Ihnat. Design and biological evaluation of substituted pyrrolo[3,2-d]pyrimidines as dual acting RTK and microtubule targeting 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 4857.