CB30865

IC50: 2.8 nM for W1L2; 156 nM for isolated mammalian TS

CB30865 is a highly potent cytotoxic agent. The compound inhibits isolated mammalian thymidylate synthase (TS), but this inhibition is insufficient to account for its cellular toxicity. Thymidylate synthase (TS) is a critical enzyme in the de novo synthesis of thymidylate (dTTP) and has long been recognized as a target for chemotherapeutic intervention.

In vitro: CB30865 was the most potent growth inhibitory agent (IC50 values in the range 1–100 nM for several mouse and human cell types). Against W1L2 cells, the analogues of CB300179 and CB300189 demonstrated reduced potency in the presence of exogenous thymidine (dThd), and against a W1L2:C1 TS overproducing cell line. In contrast, CB30865 retained activity in these systems. No cell cycle redistribution was observed following exposure (4–48 h) to an equitoxic concentration of CB30865 [1].

In vivo: The in vivo evaluation of CB30865 was hampered because of its low aqueous solubility (<1 μM at pH 6). This low aqueous solubility of CB30865 initiated a search for more water-soluble analogues to allow the in vivo evaluation of this class of compounds. It was envisaged that aqueous solubility could be increased by the introduction of amino functionalities (e.g., N-methylpiperazine) at the 2-position of the quinazolin-4-one ring [2].

Clinical trial: No clinical data are available

References:
[1] Bavetsias V, Skelton LA, Yafai F, Mitchell F, Wilson SC, Allan B, Jackman AL.  The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem. 2002;45(17):3692-702.
[2] Skelton LA, Ormerod MG, Titley J, Kimbell R, Brunton LA, Jackman AL.  A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus. Br J Cancer. 1999;79(11-12):1692-701.