Pirtobrutinib (LOXO-305) is an advanced BTK inhibitor that displays high selectivity and operates through a non-covalent mechanism. This compound effectively inhibits various BTK C481 substitution mutations, leading to tumor regression in BTK-dependent lymphoma tumors in mouse xenograft models. Furthermore, Pirtobrutinib exhibits remarkable selectivity for BTK, with more than a 300-fold difference compared to 370 other kinases tested. Notably, at a concentration of 1 μM, Pirtobrutinib demonstrates no significant inhibition of non-kinase off-targets.

Pirtobrutinib以nM级的效力强效抑制了野生型BTK及BTK C481S介导的激酶活性。Pirtobrutinib对WT BTK (Y223) 自磷酸化显示出强烈的抑制作用，其IC50为3.68 nM。同样，Pirtobrutinib对BTK C481S Y223、C481T Y223以及C481R Y223的自磷酸化也表现出显著抑制，其IC50分别为8.45、7.23和11.73 nM[1]。