Unmet Medical Needs

As the understanding of clinical resistance to current antifolate therapy increases, new molecules designed to overcome these challenges have and will continue to emerge. Antifolates that do not utilize the RFC, and are not substrates for FPGS will potentially meet this need. Also, compounds that do not induce the synthesis of their target enzymes will be valuable tools. Recent work directed at finding molecules that use the MFR rather than the RFC has been reported. The ubiquitous expression of the RFC in normal tissue reduces patient tolerability of antifolates utilizing this transporter. MFR-a, however, is overexpressed on some tumors, and has limited distribution in normal tissue. CB300638 (35) has proven to be a potent inhibitor of TS and has shown high affinity for MFR-a while at the same time having low affinity for the RFC.108 One challenge to developing an agent targeted towards tumors overexpressing MFR-a would be the need to stratify patients based on an individual's particular tumor MFR-a expression. It is known however that 90% of ovarian cancers overexpress MFR-a.

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