Irreversible dual inhibitory mode: The novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma

Ning Ding, Xitao Li, Yunfei Shi, Lingyan Ping, Lina Wu, Kai Fu, Lixia Feng, Xiaohui Zheng, Yuqin Song, Zhengying Pan, Jun Zhu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15122-15136
Number of pages15
JournalOncotarget
Volume6
Issue number17
DOIs
StatePublished - 2015

Keywords

  • B-cell lymphoma
  • BCR signaling
  • Btk
  • Irreversible inhibitor
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology

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