The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.

中文翻译：

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用于靶向光活化化学疗法的光开关抗代谢物

全身给药的抗癌药物的疗效和耐受性受到其脱靶效应的限制。对其细胞毒活性的精确时空控制将允许改善化疗治疗，而光调节药物非常适合此目的。我们开发了光氨蝶呤，这是人类二氢叶酸还原酶 (DHFR) 的第一种光开关抑制剂，作为甲氨蝶呤的光致变色类似物，甲氨蝶呤是一种广泛用于治疗癌症和银屑病的化疗药物。对斑马鱼中光调节的 DHFR 酶活性、细胞增殖和体内效应的量化表明，光氨蝶呤在其光活化顺式构型中表现为一种有效的抗叶酸剂，并且在其暗放松的反式中几乎没有活性。因此，