Table 4 Representative non-covalent BTK inhibitors in preclinical stage

XMU-MP-3

C₂₇H₂₇F₃N₈O

XMU-MP-3 is a potent BTK inhibitor with IC50 of 10.7 nM for WT BTK. It also effectively inhibits C481S mutant BTK in vitro. XMU-MP-3 suppresses the proliferation of BTK-transformed Ba/F3 cell with an IC50 of 11.4 nM. It remains active against C481S mutant BTK-transformed Ba/F3 cells with an IC50 of 182.3 nM

XMU-MP-3 remarkably inhibits tumor growth in BTK-transformed Ba/F3 and Ramos in mouse xenograft models without affecting animal weights

[65]

CB1763 (also known as AS-1763)

NA

NA

CB1763 potently, reversibly inhibits both WT and C481S mutant BTKs (IC50 = 0.85 and 0.99 nM for WT and C481S, respectively). CB1763 substantially reduces BTK Tyr223 autophosphorylation at nanomolar concentration in HEK293 cells that are transfected with C481S mutant BTK

CB1763 shows excellent antitumor activity in the BTK-driven OCI-Ly10 xenograft model

[92]

GNE-431

C₃₀H₃₂N₁₀O₂

GNE-431 potently inhibits WT BTK and C481S mutant BTK (IC50 = 3.2 and 2.5 nM for WT and C481S mutant, respectively). Additionally, GNE-431 shows high potency against several other BTK mutants including C481R, T474I, and T474M mutants (IC50 = 7.5–10 nM). GNE-431 potently suppresses BTK autophosphorylation in C481S BTK mutant-transfected cells

No in vivo data regarding the activity of GNE-431 in B cell malignancies to date

[66]

CGI-1746

C₃₄H₃₇N₅O₄

By occupying an H3 binding pocket, CGI-1746 stabilizes an inactive conformation of BTK. CGI-1746 reversibly and selectively inhibits BTK with IC50 of 8.9 nM and 16 nM for WT BTK and C481S mutant, respectively. CGI-1746 induces significant cell cycle arrest of Ramos cells in vitro

No in vivo data regarding the activity of CGI-1746 in B cell malignancies to date

[67, 93]