BMS-986142 / BMS - LARVOL DELTA

A large-scale human toxicogenomics resource for drug-induced liver injury prediction. (PubMed, Nat Commun) - "It flagged recent phase III clinical failures, including Evobrutinib, TAK-875, and BMS-986142, overlooked by animal studies. Unlike single-endpoint readouts-even from 3D models-transcriptomics offers a multi-dimensional system-level view of hepatocyte responses, capable of detecting diverse DILI mechanisms not captured by conventional assays. Scalable, actionable, and integrated into a broader AI/ML drug discovery platform, this work establishes toxicogenomics as a promising tool for developing safer therapeutics and addressing one of the most pressing challenges in toxicology."

Journal • Hepatology • Liver Failure

Multiple shots on goal: dual approaches to the design of inhibitors of Bruton's tyrosine kinase (BTK) that advanced into clinical studies (ACS-Fall 2025) - "The second part of the presentation 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, branebrutinib was advanced into clinical studies."

Clinical • Metastases • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • BTK

Evaluation of BMS-986142, a reversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study. (PubMed, Lancet Rheumatol) - P2 | "Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis."

Journal • P2 data • Cardiovascular • Endometrial Adenocarcinoma • Endometrial Cancer • Gastrointestinal Disorder • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • Solid Tumor

Structural journey in the discovery of BTK inhibitors BMS-986142 and branebrutinib, from an early nicotinamide lead to advanced carbazole and dimethylindole cores (ACS-Fall 2022) - "Structure-based design from a nicotinamide core led to the carbazole series of inhibitors that set the stage for the discovery of BMS-986142, a non-covalent, reversible inhibitor of BTK. Further structure- and property-based modifications to the carbazoles afforded the indole-carboxamide scaffold, which was a key step in the discovery of the covalent, irreversible BTK inhibitor, branebrutinib."

Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology

Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors. (PubMed, Bioorg Chem) - "In this article, we designed and synthesized pyrrolo[1,2-a]quinoxalin-4(5H)-one and imidazo[1,2-a]quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities...In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo."

Journal • Immunology • Oncology

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease. (PubMed, Cancers (Basel)) - "However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564...These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders...By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help..."

Journal • Review • CNS Disorders • Complement-mediated Rare Disorders • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Multiple Sclerosis • Novel Coronavirus Disease • Oncology • Rheumatoid Arthritis • Rheumatology • Thrombocytopenia • Thrombocytopenic Purpura

Measuring atropisomers of BMS-986142 using 2DLC as an enabling technology. (PubMed, J Pharm Biomed Anal) - "Excellent precision (relative standard deviation of 0.3 %) and recovery (101.2 ± 0.2 %) was achieved for an atropisomer impurity at a 10 % monitoring level in the first configuration with sensitivity down to 0.2 % w/w. With the second instrument configuration, which eliminated the need for fraction recombination, similar figures of merit were maintained for the second dimension at the cost of losing the ability to collect and park multiple fractions."

Journal • Immunology

Advancing stereoisomeric separation of an atropisomeric Bruton's tyrosine kinase inhibitor by using sub-2 µm immobilized polysaccharide-based chiral columns in supercritical fluid chromatography. (PubMed, J Chromatogr A) - "Separation of BMS-986142 atropisomers has been successfully achieved on an achiral polar-embedded C18 column in reversed-phase liquid chromatography (RPLC) and on polysaccharide-based chiral columns in RPLC and supercritical fluid chromatography (SFC)...Furthermore, our study suggests that the contribution to band broadening from the extra column volume (ECV) of modern commercial SFC instrument was not negligible for a 3.0 mm I.D. × 100 mm column packed with 1.6 μm particles. This result reaffirms that there is a great need for further improvement of SFC instrument design in order to realize the full theoretical efficiency of both sub-2 μm achiral and chiral columns."

Journal

"Dr Steven Wisniewski @bmsnews talking about atropisomerism and the synthesis of the BTK inhibitor BMS-986142 #OPRDNA19" (@SciUp)