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Microtubules are cytoskeleton protein polymers composed of αß-tubulin heterodimers which play pivotal roles in cell division, cellular transport and cell signaling. Interfering with microtubule dynamics is a well-established strategy for the treatment of cancer. However, clinical utility of microtubule targeting agents (MTAs) in cancer chemotherapy is often limited by the emergence of drug resistance. Expression of P-glycoprotein (Pgp) or the βIII isotype of tubulin, are two clinically established drug resistance mechanisms. We previously reported that compound AG346 binds to the colchicine site of tubulin and has microtubule depolymerization activity in A-10 cells (EC50 = 365 nM). Molecular modeling and docking studies of this compound in the X-ray crystal structure of tubulin (PDB: 402B) suggested that the pyrrole NH can be substituted with alkyl chains of optimal length to obtain an altered binding conformation which can facilitate interaction with the hydrophobic pocket formed by amino acid Val181 of side chain A, and Lys352 and Thr314 of side chain B. We designed and synthesized a variety of pyrrole NH-alkyl substituted compounds and determined that the compound AG473 shows a 43-fold improved microtubule depolymerization potency (EC50 = 8.4 nM) in A-10 cells, compared to the lead compound. In addition, this compound inhibited the growth of human melanoma cancer cell line MDA-MB-435 in culture with an IC50 of 7.2 nM, which is a 5-fold improvement in potency over the parent compound. These analogs also circumvented resistance mediated by Pgp and βIII-tubulin. These attributes provide the impetus for further preclinical development of these compounds as microtubule targeted antitumor agents in vivo and these studies are currently underway. Citation Format: Aleem Gangjee, Tasdique M. Quadery, Susan L. Mooberry. Structure-activity relationship study of pyrrolo[2,3- d]pyrimidines as microtubule targeting antitumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5105. doi:10.1158/1538-7445.AM2017-5105