balicatib (AAE581) / Novartis - LARVOL DELTA

Calpain-2 inhibition prevents pressure overload-induced lysosomal cathepsin release and cardiac hypertrophy. (PubMed, Life Sci) - "These findings identify calpain-2-mediated LAMP2 proteolysis as an upstream trigger linking lysosomal dysfunction to pathological hypertrophy, and highlight selective calpain-2 inhibition as a therapeutic strategy for heart failure treatment."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Targeted Protein Degradation • CAPN2 • CTSB • CTSS • LAMP2

Unraveling the pyroptosis pathway: Key insights into methotrexate-induced liver injury. (PubMed, Biochem Pharmacol) - "In vitro, scavenging ROS with N-acetylcysteine (NAC) and inhibiting mPTP opening with ciclosporin A (CsA) markedly suppressed pyroptosis by alleviating mitochondrial dysfunction, reducing ROS accumulation, restoring mitochondrial membrane potential, and preserving mitochondrial ultrastructure. Furthermore, Connectivity Map analysis predicted four potential therapeutic agents, including RS-127445, SB-218795, proadifen, and balicatib. Collectively, these findings demonstrate that MTX induces NLRP3-dependent pyroptosis through ROS accumulation and sustained mPTP opening."

Journal • Hepatology • Liver Failure • Metabolic Disorders • IL18 • IL1B • NLRP3 • PARP12

Electrochemical Synthesis of Unnatural Amino Acids via Anodic Decarboxylation of N-Acetylamino Malonic Acid Derivatives. (PubMed, Org Lett) - "The decarboxylative cyclization proceeds under constant current conditions in an undivided cell in an aqueous medium without any added base. A successful bioisosteric replacement of the 1-aminocyclohexane-1-carboxylic acid subunit by the THP-containing amino acid scaffold in cathepsin K inhibitor balicatib helped to reduce lipophilicity while retaining low nanomolar enzyme inhibitory potency and comparable microsomal stability."

Journal • CTSK

Morphea after covid 19 vaccine : A new case report (EADV-Sp 2022) - "In adults, a drug or traumatic factors have been invoked in a few observations with lesions localized at the injection sites (vitamin K, vitamin B12, pentazocine...) or at a distance (bisoprolol, bleomycin, peplomycin, D penicillamine, balicatib, recombinant interleukin 2, L-5-hydroxytryptophan and carbidopa...). Treatment is based on clinical subtype and extent of involvement. Our patient was put on oral corticosteroids and methotrexate with a good clinical evolution."

Clinical • Fibrosis • Immunology • Infectious Disease • Novel Coronavirus Disease • Pain • IL2

A patent review on cathepsin K inhibitors to treat osteoporosis (2011 - 2021). (PubMed, Expert Opin Ther Pat) - "The most notable cases of drug candidates targeting CatK were balicatib and odanacatib, which reached Phase II and III clinical trials, respectively, but did not enter the market. Further developments include exploring new chemical entities beyond the nitrile-based chemical space, with improved ADME and safety profiles. In addition, CatK's role in cancer immunoexpression and its involvement in the pathophysiology of osteo- and rheumatoid arthritis have raised the race to develop activity-based probes with excellent potency and selectivity."

Journal • Review • Immunology • Inflammatory Arthritis • Oncology • Osteoporosis • Rheumatoid Arthritis • Rheumatology • CTSK

Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway. (PubMed, Cells) - "Further, inactivating CTSK using balicatib, a pharmacological cell-permeable inhibitor of CTSK, resulted in IOP elevation due to increased levels and excessive deposition of ECM-like collagen-1A in the TM outflow pathway...Contrarily, constitutive expression of CTSK decreased ECM and increased actin depolymerization by decreasing phospho-cofilin, negatively regulated the availability of active TGFβ2, and reduced the levels of alpha-smooth muscle actin (αSMA), indicating an antifibrotic action of CTSK. In conclusion, these observations, for the first time, demonstrate the significance of CTSK in IOP regulation by maintaining the ECM homeostasis and actin cytoskeleton-mediated contractile properties of the TM outflow pathway."

Journal • Fibrosis • CTSK • Fascin • TGFB1 • TGFB2 • VCL

Inhibitory effect of cathepsin K inhibitor (ODN-MK-0822) on invasion, migration and adhesion of human breast cancer cells in vitro. (PubMed, Mol Biol Rep) - "Previous studies on the role of cathepsin K (CTSK) in metastatic spreading led to several strategies for inhibition of this molecule such as MIV-711 (Medivir), balicatib and odanacatib (ODN) which were on trial in the past. ODN exerts anti-metastatic action through inhibition of signaling pathway for MMP-9, PI3K and MAPK. This indicates potential therapeutic effects of ODN in the treatment of metastatic breast cancer."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • MAPK8 • MMP9 • PXN • RAC1 • TIMP1

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis. (PubMed, Br J Clin Pharmacol) - "The extensive clinical program for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: 1) provide sustained reductions in resorption markers, increases in BMD, and demonstrated fracture risk reduction; 2) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and 3) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme) which may yield transient increases in resorption following treatment discontinuation and the potential for non-monotonic responses at sub-therapeutic doses."

Clinical • Journal • Review