lfm-a13 and Thromboembolism

Targeting Bruton's tyrosine kinase (BTK) with a small molecule inhibitor may be useful in treatment of BTK-expressing malignancies because of the anti-apoptotic function of BTK in cancer cells. Furthermore, BTK inhibitors also exhibit anti-thrombotic properties that may be desirable in the context of the increased risk of thromboembolic complications in cancer patients. This review will focus on the role of BTK in drug resistance in cancer, thromboembolism, and various pathologic immune responses, such as graft versus host disease. The therapeutic potential of targeting BTK is illustrated by discussion of the biologic activity profile of the rationally designed BTK inhibitor LFM-A13.

Topics: Agammaglobulinaemia Tyrosine Kinase; Amides; Antineoplastic Agents; Apoptosis; Drug Design; Humans; Leukemia; Nitriles; Protein-Tyrosine Kinases; Thromboembolism

The specific inhibitor of the protein tyrosine kinase, Bruton's tyrosine kinase (BTK), alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, CAS 244240-24-2), is a chemosensitizing antileukemic agent with antithrombotic properties. Oral formulation of LFM-A13 (LFM-A13-F) did not cause acute, subacute or chronic toxicity in mice at dose levels up to 200 mg/kg. The in vivo antithrombotic activity of LFM-A13 was studied in a mouse model of collagen-induced fatal thromboembolism. Oral doses of LFM-A13-F dose dependently prevented collagen-induced thromboembolism in mice without causing bleeding. LFM-A13 could be combined with dipyridamole (CAS 58-32-2) without side effects. These results indicate that LFM-A13 may be particularly useful in the treatment of leukemia patients who are at risk for thromboembolic complications.

Topics: Administration, Oral; Amides; Animals; Bleeding Time; Blood Cell Count; Blood Coagulation; Collagen; Dipyridamole; Female; Fibrinolytic Agents; Mice; Mice, Inbred BALB C; Nitriles; Platelet Aggregation Inhibitors; Thromboembolism

The leflunomide metabolite analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK) which plays an important role in platelet physiology by regulating the glycoprotein GPVI-FcRgamma-coupled collagen receptor signaling pathway. At low micromolar concentrations, LFM-A13 inhibited collagen-induced ultrastructural changes indicative of activation. LFM-A13 inhibited collagen (but not thrombin, TRAP-6, or ADP)-induced platelet aggregation in a concentration-dependent fashion with an IC50 value of 2.8 microM. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 1 to 100 mg/kg. At nontoxic dose levels, LFM-A13 prolonged the tail bleeding times of mice and improved event-free survival in two mouse models of agonist-induced invariably fatal pulmonary thromboembolism. To our knowledge, LFM-A13 is the first anti-thrombotic agent which prevents platelet aggregation by inhibiting BTK.

Topics: Adenosine Diphosphate; Agammaglobulinaemia Tyrosine Kinase; Amides; Animals; Aspirin; Bleeding Time; Catalytic Domain; Collagen; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Fibrinolytic Agents; Humans; Janus Kinase 3; Male; Mice; Mice, Inbred ICR; Nitriles; Peptide Fragments; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein-Tyrosine Kinases; Pulmonary Embolism; Quinazolines; Receptors, Collagen; Signal Transduction; Thrombin; Thromboembolism; Thromboplastin