Advancements in BTK Inhibition: The Profile of REDX08608 for Overcoming Resistance in B-Cell Malignancies

REDX08608 is a novel, potent, and selective reversible Bruton's tyrosine kinase (BTK) inhibitor that demonstrates equal potency against both wild-type and mutant C481S BTK. BTK is crucial in the BCR signaling pathway for B-cell development, activation, and survival and is a validated target for treating B-cell malignancies such as CLL and NHL. Existing BTK inhibitors like ibrutinib, acalabrutinib, and GS-4059 are irreversible and covalent, binding to a cysteine residue C481 in BTK, but mutations at this site can lead to drug resistance.

The REDX08608 inhibitor has been designed to overcome resistance by targeting both wild-type and mutated BTK. It has shown superior pharmacokinetics and reversibly inhibits BTK with nanomolar binding affinity. REDX08608 effectively inhibits BTK signaling and growth in cell lines reliant on the BTK pathway, including the OCI-LY10 ABC-DLBCL cell line, and also operates in primary CLL cells.

In human whole blood and PBMCs, REDX08608 inhibits B-cell activation at nanomolar concentrations, as measured by the inhibition of CD69 in CD19+ cells. The compound is highly selective, with over 100-fold selectivity against other Tec and Src kinase family members and over 400-fold selectivity against EGFR.

REDX08608 has been thoroughly profiled in DMPK in vitro assays, showing acceptable metabolic and plasma stability across species. It does not activate PXR or exhibit time-dependent inhibition, and it has high IC50 values for several human cytochrome P450s. The compound has demonstrated good exposure, oral bioavailability, and half-life in preclinical species, with dose linearity assessed in mouse, rat, and dog models.

REDX08608's in vivo efficacy will be disclosed, highlighting its potential as a reversible BTK inhibitor that could target both wild-type BTK and address resistance mechanisms in patients with CLL who progress after ibrutinib treatment.