Table 3.
Non-covalent BTK inhibitors.
| Pirtobrutinib (LOXO-305) | MK-1026 (formerly ARQ-531) | CG-806 | Fenebrutinib (GDC-0853) | Vecabrutinib (SNS-062) | |
|---|---|---|---|---|---|
| Company | Eli Lilly | Merck | Aptose | Genentech | Sunesis |
| IC50* | 3.15 nM (BTK WT) | 0.85 nM (BTK WT) | 8.4 nM (BTK WT) | 0.91 nM (BTK WT) | 3 nM (BTK WT)# |
| 1.42 nM (BTK C481) | 0.39 nM (BTK C481) | 2.5 nM (BTK C481) | 1.6 nM (BTK C481S) | ||
| 0.8 nM (FLT3-ITD) | 1.3 nM (BTK C481R) | ||||
| Biochemical IC50 (Selectivity)* | BTK C481 1.42nM (1x) | BTK C481 0.39nM (1x) | BTK C481 2.5nM (1x) | BTK WT 2.3nM (1x) | BTK WT 3nM (1x) |
| ITK 103nM (3521x) | ITK >10,000nM (>10,000x) | ITK 4.2nM (1.7x) | ITK >1,000nM (>400x) | ITK 14nM (5x) | |
| EGFR >1,000nM (>700x) | TEC 5.8nM (14.9x) | EGFR >1,000nM (>400x) | EGFR >1,000nM (>400x) | EGFR, not specified | |
| TEC 1,234nM (869x) | LYN 19nM (48.7x) | TEC >1,000nM (>400x) | TEC 1,000nM (>400x) | TEC 14nM (5x) | |
| SYK, not specified | |||||
| MEK1/ERK, indirect | |||||
| Clinical trials in CLL and B cell malignancies | Phase 1, 2 | Phase 1, Phase 2 pending | Phase 1 | Phase 1 | Phase 1 |
| Comment | Highly selective | Active against PLCG2 mutation | Potent inhibitor of BTK and FLT3-ITD | Highly selective, Withdrawn from clinical development in B cell malignancies | Withdrawn from clinical development in B cell malignancies |
| References | (129) | (128, 130) | (131) | (132–134) | (135) |
*IC50 and fold selectivity over wild-type BTK (fenebrutinib and vecabrutinib) or mutant BTK (all others) within each BTK inhibitor; not for comparison across BTK inhibitors.
#IC50 for BTK C481 has not been reported.
BTK, Bruton’s tyrosine kinase; EGFR, epidermal growth factor receptor; FLT3-ITD, FMS-like tyrosine kinase 3 with internal tandem duplication; IC50, half maximal inhibitory concentration; ITK, Interleukin-2-Inducible T-cell Kinase; LYN, LYN tyrosine kinase; SYK, spleen tyrosine kinase; TEC, TEC kinase; WT, wild-type.