Key differences between available cBTKis and pirtobrutinib
| . | Ibrutinib . | Acalabrutinib . | Zanubrutinib . | Pirtobrutinib . |
|---|---|---|---|---|
| BTK binding | Covalent | Covalent | Covalent | Reversible |
| C481 | C481 | C481 | ATP pocket | |
| Distant from C481 | ||||
| Half-life | 6 hours | 1 hour | 4 hours | 20 hours >90% BTK inhibition |
| BTK Y223 autophosphorylation | Inhibited | Inhibited | Inhibited | Inhibited |
| BTK Y551 phosphorylation | No effect | No effect | No effect | Inhibited (maintenance of closed conformation) |
| BTK C481S mutation | Common | Reported | Reported | Not described Effective against C481S |
| Kinase-dead mutations | Uncommon and restricted to C481∗ (active against HCK) | Not reported to date | Reported: L528W > C481Y | Reported: L528W > V416L, A428D, C481R, M477I, and M437R |
| T474I/T474L gatekeeper mutation | Uncommon∗; active against T474I and T474L | Reported | Not reported to date | Reported |
| Off-target hits† | BLK | HER4 | BLK | HER4 |
| BMX | BMX | BRK | ||
| BRK | BRK | |||
| EGFR | EGFR | |||
| HER2 | HER4 | |||
| HER4 | RLK | |||
| ITK | ||||
| JAK3 | ||||
| RLK | ||||
| TEC | ||||
| References | 2,6-12 | 3,13-15 | 4,7,16 | 8,17-19 |
| . | Ibrutinib . | Acalabrutinib . | Zanubrutinib . | Pirtobrutinib . |
|---|---|---|---|---|
| BTK binding | Covalent | Covalent | Covalent | Reversible |
| C481 | C481 | C481 | ATP pocket | |
| Distant from C481 | ||||
| Half-life | 6 hours | 1 hour | 4 hours | 20 hours >90% BTK inhibition |
| BTK Y223 autophosphorylation | Inhibited | Inhibited | Inhibited | Inhibited |
| BTK Y551 phosphorylation | No effect | No effect | No effect | Inhibited (maintenance of closed conformation) |
| BTK C481S mutation | Common | Reported | Reported | Not described Effective against C481S |
| Kinase-dead mutations | Uncommon and restricted to C481∗ (active against HCK) | Not reported to date | Reported: L528W > C481Y | Reported: L528W > V416L, A428D, C481R, M477I, and M437R |
| T474I/T474L gatekeeper mutation | Uncommon∗; active against T474I and T474L | Reported | Not reported to date | Reported |
| Off-target hits† | BLK | HER4 | BLK | HER4 |
| BMX | BMX | BRK | ||
| BRK | BRK | |||
| EGFR | EGFR | |||
| HER2 | HER4 | |||
| HER4 | RLK | |||
| ITK | ||||
| JAK3 | ||||
| RLK | ||||
| TEC | ||||
| References | 2,6-12 | 3,13-15 | 4,7,16 | 8,17-19 |
ATP, adenosine triphosphate; HCK, hematopoietic cell kinase.
With the exception of RT, in which T474I, T474S, and L528W have been reported at progression on ibrutinib.20
For ibrutinib, acalabrutinib, and zanubrutinib, derived from review by Estupiñán et al,12 >80% inhibition at clinical doses; for pirtobrutinib, listed kinases have <20-fold selectivity relative to BTK, as reported by Gomez et al.19