Abstract
Abstract RFC is a ubiquitously expressed folate transporter that is present in normal tissues and tumors. RFC is utilized by reduced folates and by all the clinically used classical antifolates. In contrast, PCFT shows more limited expression in normal tissues and is highly effective in folate transport under low pH conditions associated with hypoxic solid tumors. Antifolates that are selectively transported by PCFT over RFC offer significant promise for development of targeted therapies of tumors (over)expressing PCFT. We previously reported 6-substituted pyrrolo[2,3-d]pyrimidines and thieno[2,3-d]pyrimidines as part of a continued effort to elucidate the SAR for substrate binding and cellular uptake for RFC, PCFT as well as folate receptors (FRs). While the X-ray crystal structure of FRs bound to antifolates has been resolved, the absence of X-ray crystal structures of PCFT and RFC has hindered structure-based medicinal chemistry efforts for development of antifolates selectively transported by PCFT. To address this, pharmacophore models were developed for the first time using Discovery Studio for PCFT and RFC using a series of thirty six 6-substituted bicyclic pyrrolo[2,3-d]pyrimidines and/or thieno[2,3-d]pyrimidines that included highly potent and selective compounds such as AGF94 (PCFT = 0.3 nM; RFC = 101 nM) previously reported by us. Compounds used for model development displayed a 3-log range inhibition of cancer cells overexpressing PCFT or RFC. The best models display a 4-point pharmacophore with excellent regression values (r2 PCFT = 0.96; RFC = 0.92). The models were internally validated by leave-one-out analysis (q2 PCFT = 0.752; RFC = 0.59) and externally validated using a test set of 6-substituted bicyclic analogs not used in model development. Comparison of the pharmacophore models indicates different conformational and structural requirements for compounds for binding to PCFT or RFC. We have used these models to explain the potent PCFT inhibitory activity and selectivity of compounds such as AGF94. These models are being used in the development of selectively transported targeted antifolates that would result in decreased toxicity compared to standard antifolates such as methotrexate (MTX) or pemetrexed (PMX) which utilize all three folate transport systems. Citation Format: Sudhir Raghavan, Aleem Gangjee, Larry H. Matherly. Novel proton coupled folate transporter (PCFT) and reduced folate carrier (RFC) pharmacophore models for development of transporter-selective antifolates. [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 1362.
Published Version
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