Pirtobrutinib is a highly selective, non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, with IC50 values of 3.2nM and 1.4nM for BTK and BTKC481S, respectively [1]. Pirtobrutinib can effectively inhibit the self-phosphorylation of BTK at the tyrosine 223 (Y223) site and the related downstream signaling pathways, and can reduce the phosphorylation at the upstream tyrosine 551 (Y551) site[2]. Pirtobrutinib has been widely used to inhibit chronic B-cell malignancies and platelet signal transduction and function[3].
In vitro, Pirtobrutinib treatment for 72 hours significantly inhibited the proliferation of TMD8 cells and REC-1 cells, with IC50 values of 6.4nM and 3.1nM, respectively[4]. Treatment with Pirtobrutinib (0.5μM) for 36 hours significantly inhibited the release of p-ERK1/2 and ERK1/2-driven inflammatory cytokines in BCWM.1 cells expressing BTKC481S [5]. Treatment with Pirtobrutinib (1μM) for 24 hours significantly inhibited the overall DNA and RNA synthesis in MEC-1 cells that expressed BTKC481S [6].
References:
[1] Gomez E B, Ebata K, Randeria H S, et al. Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor[J]. Blood, The Journal of the American Society of Hematology, 2023, 142(1): 62-72.
[2] Molica S, Allsup D. Pirtobrutinib in Chronic Lymphocytic Leukemia: Navigating Resistance and the Personalisation of BTK-Targeted Therapy[J]. Cancers, 2025, 17(18): 2974.
[3] Bye A P, Kriek N, Sage T, et al. Pirtobrutinib results in reversible platelet dysfunction compared to ibrutinib and acalabrutinib[J]. Haematologica, 2022, 108(5): 1429.
[4] Keam S J. Pirtobrutinib: First Approval[J]. Drugs, 2023, 83(6).
[5] Munshi M, Liu X, Kofides A, et al. ERK1/2 pro‐survival signalling is suppressed by pirtobrutinib in ibrutinib‐resistant MYD88‐mutated lymphoma cells[J]. British Journal of Haematology, 2024, 205(5): 1866-1872.
[6] Aslan B, Kismali G, Iles L R, et al. Pirtobrutinib inhibits wild-type and mutant Bruton’s tyrosine kinase-mediated signaling in chronic lymphocytic leukemia[J]. Blood cancer journal, 2022, 12(5): 80.
Pirtobrutinib是一种高选择性、非共价、可逆的Bruton's tyrosine kinase (BTK)抑制剂，对BTK和BTKC481S的IC50值分别为3.2nM和1.4nM[1]。Pirtobrutinib能有效抑制BTK在酪氨酸223位点的自身磷酸化及相关的下游信号通路，并能减少上游酪氨酸551位点的磷酸化[2]。Pirtobrutinib已被广泛用于抑制慢性B细胞恶性肿瘤以及血小板信号转导和功能[3]。
在体外，Pirtobrutinib处理72小时显著抑制了TMD8细胞和REC-1细胞的增殖，IC50值分别为6.4nM和3.1nM[4]。使用0.5μM的Pirtobrutinib处理表达BTKC481S的BCWM.1细胞36小时，显著抑制了p-ERK1/2以及ERK1/2驱动的炎症细胞因子的释放[5]。使用1μM的Pirtobrutinib处理表达BTKC481S的MEC-1细胞24小时，显著抑制了细胞总的DNA和RNA合成[6]。