Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma
Metrics: PDF 3116 views | HTML 3693 views | ?
Ning Ding1, Xitao Li2, Yunfei Shi3, Lingyan Ping1, Lina Wu4, Kai Fu5, Lixia Feng1, Xiaohui Zheng1, Yuqin Song1, Zhengying Pan2 and Jun Zhu1
1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing, China
2 Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Shenzhen, China
3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China
4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Central Laboratory, Peking University Cancer Hospital and Institute, Beijing, China
5 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
Jun Zhu, email:
Zhengying Pan, email:
Yuqin Song, email:
Keywords: BCR signaling, Btk, irreversible inhibitor, targeted therapy, B-cell lymphoma
Received: December 17, 2014 Accepted: March 26, 2015 Published: April 14, 2015
The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.