Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric occupancy of inhibitor binding sites results in partial inhibition, this effect is overrun by a concomitant activation of unliganded binding sites. Therefore, when an inhibitor of a cooperative enzyme does not reach saturating levels, a common scenario during drug administration, it may cause the contrary of the desired effect. The implications for drug development are discussed.

中文翻译：

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通过亚化学计量抑制激活。


令人震惊的报告描述了当小分子抑制剂特异性灭活 BRAF V600E 蛋白激酶而不是 wt-BRAF 时，人促细胞分裂原激活蛋白激酶途径的矛盾触发。我们使用细菌和人类 HtrA 蛋白酶作为模型，对“抑制激活”这一普遍现象进行了概念分析。我们的数据提出了基于变构和协同的经典生化原理的清晰解释。尽管抑制剂结合位点的亚化学计量占据导致部分抑制，但这种效应会因未配体结合位点的伴随激活而超出。因此，当协同酶的抑制剂未达到饱和水平（给药期间的常见情况）时，可能会导致与预期效果相反的情况。讨论了对药物开发的影响。