Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton’s Tyrosine Kinase (BTK)

Abstract

Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants

“…The initial dose selection was made to achieve a low level of BTK occupancy based on several considerations, including regulatory requirements for safety relative to animal toxicology, in vitro characterisation of BTK inactivation rates, estimated BTK t 1/2 , preclinical drug stability assays, PK/PD modelling and data from nonhuman primate studies 21 . The maximum recommended starting dose based on the no‐observed‐AE level and a 10‐times safety margin was 19 mg.…”

“… 21 Potent efficacy across a range of measures (e.g. reduction in proteinuria) was also observed in a mouse model of lupus nephritis, with robust inhibition of BTK activity at doses as low as 0.2 mg kg −1 21 …”

“…Branebrutinib (BMS‐986195) is a potent, highly selective, small‐molecule, covalent inhibitor of BTK that can be administered orally. It covalently modifies a cysteine residue in the active site, resulting in rapid inactivation of BTK 21 . Branebrutinib has demonstrated >5000‐fold selectivity for BTK over 240 other kinases, with only 4 related Tec family kinases demonstrating selectivity of <5000‐fold 21 .…”

“…It covalently modifies a cysteine residue in the active site, resulting in rapid inactivation of BTK 21 . Branebrutinib has demonstrated >5000‐fold selectivity for BTK over 240 other kinases, with only 4 related Tec family kinases demonstrating selectivity of <5000‐fold 21 . Robust in vivo efficacy of branebrutinib was demonstrated in murine models of collagen‐ and collagen antibody–induced arthritis, protecting against clinically evident disease, histological joint damage and bone mineral density loss 21 .…”

Acyl‐Directed ortho‐Borylation of Anilines and C7 Borylation of Indoles using just BBr3

“…[13c] Functionalisation of the C5ÀHo f indoles is important for accessing pharmaceuticals such as C4-amino-C5-functionalised indoles (e.g.B ranebrutinib). [5,22] Thet hermodynamics of C5 vs.C 3b orylation again was probed by DFT calculations which showed the C5 isomers 15A to be more stable than the C3 isomers 15B (inset, Scheme 7) for both halide and pinacol substituents.C 5 borylation of 14 was achieved in high selectivity with the pinacol boronate ester 16 formed in moderate yield (77 %in situ and 40 %p ost purification). Attempts to monitor the borylation of 14 at the BBr 2 stage were prevented by this intermediate being poorly soluble.F inally,t he ability to perform aC 5/C7 double CÀHb orylation using BBr 3 was demonstrated using 17 (made in one step from 4-aminoindole).…”