磷脂酰肌醇3-激酶a（PI3Ka）是不同癌症中突变最为常见的基因, 特别是乳腺癌、妇科肿瘤以及头颈部鳞状细胞癌。该基因的突变遍布全段，但螺旋和激酶结构域热点突变占据着主导地位。通过alpelisib的疗效评估，该药物对野生型和突变型酶显示了等效活性，确立了选择性对isoform的PI3Ka抑制对肿瘤的治疗益处。然而，对野生型PI3Ka的抑制与严重高血糖和皮疹有关，这限制了alpelisib的使用，并提示有针对性地靶向突变型PI3Ka可能会减少毒性并提高疗效。本文介绍了STX-478，一种特异性靶向常见PI3Ka螺旋和激酶结构域突变肿瘤的变构PI3Ka抑制剂。STX-478在人类肿瘤异种移植模型中显示出强大的疗效，而不引起alpelisib所观察到的代谢紊乱。 STX-478与fulvestrant和/或cyclin-dependent kinase 4/6抑制剂的联合应用耐受良好，并在ER + HER2-异种移植肿瘤模型中提供了强大而持久的肿瘤消退效果。

Phosphoinositide 3-kinase a (PI3Ka) is one of the most mutated genes across cancers, especially breast, gynecological, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Ka inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Ka is associated with severe hyperglycemia and rash that limits alpelisib use and suggests that selectively targeting mutant PI3Ka could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Ka inhibitor that selectively targets prevalent PI3Ka helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.