BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to α-Folate Receptor–Overexpressing Tumors

Abstract

BGC 945 is a cyclopenta [g]quinazoline-based, thymidylate synthase inhibitor specifically transported into A-folate receptor (A-FR)-overexpressing tumors. Affinity of BGC 945 for the A-FR is 70% of the high-affinity ligand folic acid. In contrast to conventional antifolates, BGC 945 has low affinity for the widely expressed reduced-folate carrier (RFC). The K i for isolated thymidylate synthase is 1.2 nmol/L and the IC 50 for inhibition of the growth of A-FR-negative mouse L1210 or human A431 cells is f7 Mmol/L. In contrast, BGC 945 is highly potent in a range of A-FR-overexpressing human tumor cell lines (IC 50 f1-300 nmol/L). Pharmacokinetic variables measured following i.v. injection of 100 mg/kg BGC 945 to KB tumor-bearing mice showed rapid plasma clearance (0.021 L/h) and tissue distribution. The terminal half-lives in plasma, liver, kidney, spleen, and tumor were 2, 0.6, 5, 21, and 28 hours, respectively. Tumor BGC 945 concentration at 24 hours was f1 nmol/g tissue, at least 10-fold higher than that in plasma or normal tissues. Inhibition of thymidylate synthase in tissues leads to increased incorporation of 5-[125 I]-iodo-2V -deoxyuridine ([ 125 I]dUrd) into DNA. Forty-eight hours after injection of 100 mg/kg 6RS-BGC 945 ([ 125 I]dUrd injected at 24 hours), tumor was the only tissue with incorporation above control level (6-fold). The RFC-mediated thymidylate synthase inhibitor plevitrexed also increased uptake of [125 I]dUrd in tumor (10-fold) but, in contrast, also caused increased incorporation in other normal tissues such as spleen and small bowel (4.5-and 4.6-fold, respectively). These data suggest that BGC 945 selectively inhibits thymidylate synthase in A-FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses. (Cancer Res 2005; 65(24): 11721-8)

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

“…Moreover, the ligands use different regions of the binding cleft to accommodate the variations in the bicyclic aromatic regions. One antifolate that may take advantage of additional pockets within the binding cleft, and for which the mode of binding must await structural analysis, is the aforementioned ONX801, a molecule that contains a decorated tricyclic fused ring system (12,13,65).…”

“…Folic acid and its reduced derivatives, including 5-methyltetrahydrofolate and 10-formyltetrahydrofolate, are transported via two widely expressed facilitative transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and via a family of glycosyl-phosphatidylinositol (GPI)-anchored receptors with limited expression profiles generally described as folate receptors (FRs) (3)(4)(5)(6)(7). For >60 y, folate analogs that inhibit intracellular folate-using enzymes, termed antifolates, have been developed to treat a variety of cancer types and inflammatory diseases (8)(9)(10)(11)(12)(13)(14). More recently, the emphasis in folatemediated drug therapy has shifted to obtain a better understanding of transport mechanisms of antifolates because dose-limiting toxicities arise from their transport via RFC, and possibly PCFT, into normal cells (6,11,(15)(16)(17).…”

Redistribution of Nucleoside Transporters to the Cell Membrane Provides a Novel Approach for Imaging Thymidylate Synthase Inhibition by Positron Emission Tomography

“…6-9). Whereas the above agents inhibit both normal tissue and tumor thymidylate synthase, new antifolates, such as BGC 638 and BGC 945, are targeted to tumors via the a-folate receptor, leading to selective inhibition of tumor thymidylate synthase (6,10,11).…”

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

“…Consequently, this may allow enhanced binding of antifolates, especially those for which MFR has a binding aYnity close to folic acid. In this context, some recently identiWed novel antifolates structures, i.e., BGC638 [61] and BGC945 [15], with the property of not being a substrate for RFC but possessing a good binding aYnity for MFR, warrant further evaluation for selective MFR-mediated cell entry. Finally, recent observations that retinoic acid and histone deacetylase inhibitors can provoked a marked induction of MFR expression [41] may further facilitate selective targeting of MFR.…”

“…Although the exact role and the relative importance of the RFC in mediating antifolate antitumor activity in vivo has been fairly well established [5,29,31,50], the role of MFR is still unclear [12,67]. However, it may be anticipated that optimal MFR-mediated transport could be revealed under conditions of low extracellular folates when there is less receptor occupancy and competition with circulating reduced folates [15,61,68].…”