Table 1.

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, 7, 8, 9, 10, 11, 12	3, 13, 14, 15	4, 7, 16	8, 17, 18, 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