Table 1.
Covalent BTK inhibitors.
| Ibrutinib (PCI-32765) | Acalabrutinib (ACP-196) | Zanubrutinib (BGB-3111) | Spebrutinib (CC-292) | Tirabrutinib (ONO-4059) | |
|---|---|---|---|---|---|
| Half-life | 4-6 hours | 1 hour | 2-4 hours | 1.9 hour | 4-7 hours |
| IC50 * | 0.5nM | 5.1nM | 1.8nM | <0.5nM | 6.8nM |
| Biochemical IC50 (Selectivity)* | BTK 0.5nM (1x) | BTK 5.1nM (1x) | BTK 1.8nM (1x) | BTK 9.2nM (1x) | BTK 6.8nM (1x) |
| ITK 10.7nM (20x) | ITK >1,000nM (>1,000x) | ITK 3,277nM (>1,000x) | ITK 10,50nM (110x) | ITK >20,000nM, (>1,000x) | |
| EGFR 5.6nM (10x) | EGFR >1,000nM (>1,000x) | EGFR 606nM (336x) | EGFR >20,000nM (>1,000x) | EGFR 3,020nM (>400x) | |
| TEC 78nM (156x) | TEC 93nM (>19x) | TEC 1.9nM (1x) | TEC 8.4nM (1x) | TEC 48nM (7x) | |
| Comments | First-in-class BTKi | No ITK or EGFR inhibition | No ITK inhibition Does have TEC inhibition | Withdrawn from development | Approved in Japan for the treatment of PCNSL, WM and LPL |
| Approved dose | 420mg QD | 100mg BID | 160mg BID | Not approved | 480mg QD# |
| 560mg QD | 320mg QD | ||||
| Approved indications | CLL/SLL | CLL/SLL | MCL | Not approved | PCNSL# |
| MCL | WM# | ||||
| MZL | MCL | LPL# | |||
| WM | |||||
| Clinical trials | Phase 1, 2, 3 | Phase 1, 2, 3 | Phase 1, 2, 3 | Phase 1, 2 | Phase 1, 2 |
*IC50 and fold selectivity over BTK within each BTK inhibitor; not for comparison across BTK inhibitors.
#Approved doses and treatment indications in Japan. Tirabrutinib has not been approved in the United States.
BID, twice daily; BTK, Bruton’s tyrosine kinase; CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; IC50, half maximal inhibitory concentration; ITK, Interleukin-2-Inducible T-cell Kinase; LPL, lymphoplasmacytic lymphoma; LYN, LYN tyrosine kinase; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; PCNSL, primary CNS lymphoma; QD, once daily; SLL, small lymphocytic lymphoma; SYK, spleen tyrosine kinase; TEC, TEC kinase; WM, Waldenström’s macroglobulinemia.