REDX08608, a Novel, Potent and Selective, Reversible BTK Inhibitor with Efficacy and Equivalent Potency Against Wild-Type and Mutant C481S BTK

• Published in: Blood 2016-12, Vol.128 (22), p.4399-4399
• Main Authors: Guisot, Nicolas E.S., Best, Stuart A., Wright, Victoria, Thomason, Andrew, Woyach, Jennifer A., Mantel, Rose, McClanahan, Fabienne, Abet, Valentina, Castagna, Diana, Cousin, Peggy, Emmerich, Juliette, Ho, Kelvin, Kelly, James Russell, King-Tours, James, Lyons, Kristina, Muller, Melanie, Refuerzo, Julienne, Sargent, Louise, Talab, Fatima, Bingham, Matilda, Phillips, Caroline, Armer, Richard
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.4399.4399

Here we report the preclinical profile of REDX08608 our novel, potent and selective, reversible BTK inhibitor that is equipotent against wild-type and mutant C481S BTK. Bruton's tyrosine kinase (BTK) is a member of the src-related Tec family of cytoplasmic tyrosine kinases and plays a key role in the BCR signaling pathway, which is required for the development, activation and survival of B-cells. BTK is a clinically validated target to treat B-cell malignancies that are dependent on BCR signaling i.e.CLL and NHL with ibrutinib approved for the treatment of CLL, MCL and WM. Irreversible and covalent reversible BTK inhibitors such as ibrutinib, acalabrutinib and GS-4059 specifically target a cysteine residue C481 within BTK and mutations at this site clearly interfere with covalent drug binding. C481S, C481Y, C481R, C481F mutations have been reported and linked to cases of resistance that have emerged in patients with CLL progression following treatment with ibrutinib (Byrd2016, Inhye2016, Maddocks2015, Woaych2014). Redx reversible BTK inhibitor, REDX08608, aims to overcome this resistance mechanism by targeting both wild type and C481-mutated BTK. Redx have recently presented REDX06961 our BTK probe (Guisot2016, AACR#4795) and, following lead optimization, we are now disclosing REDX08608, our lead compound, a potent, reversible and selective BTK inhibitor, which displays an improved profile including superior pharmacokinetics. REDX08608, reversibly, inhibits WT and C481S BTK and displays nanomolar binding affinity and potency in biochemical and cellular-based assays. REDX08608 inhibits BTK signaling and growth in cell lines dependent on the BTK pathway such the OCI-LY10 ABC-DLBCL cell line. Importantly, REDX08608 also inhibits BTK signaling in primary CLL cells. In human whole blood and isolated human PBMCs, REDX08608 inhibits activation of B-cells at nanomolar concentrations measured by inhibition of immunoglobulin-induced CD69 in CD19+cells. REDX08608 is highly selective when tested against a panel of 468 kinases and exhibits improved target specificity with >100-fold selectivity against other Tec and Src kinase family members (ITK, TXK, BMX, TEC, BLK, CSK, FYN, HCK, LCK, SRC) and >400-fold selectivity against EGFR. REDX08608 was fully profiled through DMPK in vitro assays including metabolic stability, plasma stability, cytochrome P450 inhibition, PXR activation/cytochrome P450 activity, time dependent inhibition and cytochrome P450 reaction phenotyping.