PCI-32765 (ibrutinib) is an orally administered, potent and specific covalent inhibitor of Bruton's tyrosine kinase (BTK) in Phase 3 clinical development for the treatment of B cell lymphoproliferative diseases. PCI-32765 binds covalently to Cys481 of BTK, and inhibits Btk activity (IC50= 0.5 nM) in biochemical assays, and suppresses B-cell receptor (BCR) activation of primary B lymphocytes (EC50=10 nM). PCI-32765 treatments inhibit the phosphorylation of key kinases involved in the BCR signaling pathway via BTK inhibition, including PLCg, ERK and JNK (Honigberg, 2010a). In malignant B cells, PCI-32765 suppresses BCR and chemokine (CXCL12, CXCL13) activated adhesion and migration and inhibits migration of CLL, MCL and FL cells underneath stromal cells in co-culture. In addition, PCI-32765 inhibits chemokine release (CCL3, CCL4, CCL22 and CXCL13) from CLL/MCL cells in co-culture (Chang, 2011b). In vivo PK/PD studies in humans and animals demonstrate rapid covalent binding of drug to BTK. The binding remained 24 hours post drug dose despite rapid elimination of drug which results in a unique approach to improve selectivity for BTK in vivo relative to reversibly inhibited off target kinases (Advani, 2012c). Clinical results from Phase I/II studies show promising single agent activity of PCI-32765 across several NHL histologies including CLL, MCL and DLBCL (Advani, 2012c). Mechanistically, lymphocyte mobilization into the peripheral blood is notable from most patients in response to treatment with PCI-32765. Malignant B cells were decreased in Ki67, CD38 and pErk expression. This effect is likely to be related to PCI-32765 suppression of BTK activation which results in inhibition of B lymphoma chemotaxis, adherence and pseudoemperipoleisis. We propose that BTK is essential for the homing of lymphoma cells into secondary lymphoid organs, and that its inhibition results in peripheral blood compartment shift. PCI-32765 is a first-in-class covalent BTK inhibitor with demonstrated efficacies in B cell malignancies.

Biology of covalent BTK inhibitor PCI-32765 (Ibrutinib): From bench to bedside

245th National Meeting (2013)

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