PCI 29732

PCI 29732 is an inhibitor of Bruton’s Tyrosine Kinase with IC50 value of 8.2nM [1].

Bruton’s Tyrosine Kinase(BTK) belongs to the Tec tyrosine kinase family. It plays key roles in multiple cell signaling pathways. PCI 29732 inhibits BTK through interacting with the gatekeeper residue T474 of BTK and acts as an irreversible inhibitor. PCI 29732 has also been found to be potent inhibitors of Itk as well as other kinases from the Tec and Src family. In addition, PCI 29732 can block the transcriptional up-regulation of a panel of B-cell activation genes, thus inhibiting B-cell signaling and activation [1, 2].

References:
[1] Yan Lou, Timothy D. Owens, Andreas Kuglstatter, Rama K. Kondru and David M. Goldstein. Bruton’s tyrosine kinase inhibitors: approaches to potent and selective inhibition, preclinical and clinical evaluation for inflammatory diseases and B cell malignancies. J. Med. Chem. 2012, 55: 4539-4550.
[2] Lee A. Honigberg, Ashley M. Smith, Mint Sirisawad, Erik Verner, David Loury, Betty Chang, Shyr Li, Zhengying Pan, Douglas H. Thamm, Richard A. Miller and Joseph J. Buggy. The bruton tyrosine kinase inhibitor pci-32765 blocks b-cell activation and is efficacious in models of autoimmune disease and b-cell malignancy. PNAS. 2010, 107(29): 13075-13080.

Evaluation of safety and efficacy of elective PCI in patients with cardiac insufficiency.[Pubmed:28352338]

Exp Ther Med. 2017 Feb;13(2):609-613.

We analyzed the safety and the efficacy of the treatment with elective percutaneous coronary intervention (PCI) in patients with coronary heart disease complicated with cardiac insufficiency. We enrolled 217 patients diagnosed with chronic ischemic heart disease complicated with cardiac failure. According to the type of treatment they received, patients were divided into 3 groups: i) The conservative treatment group with 60 patients (they received standard medication); ii) the early PCI group with 82 cases (their condition was stabilized, surgical risk was assessed and PCI was taken as early as possible); and iii) the advanced PCI group with 75 cases (ischemic myocardium was corrected and then elective PCI was applied and for aggravated myocardial ischemia cases, PCI was applied after assessing the risk of surgery). Follow-up visits were set for approximately 3 years and clinical outcomes were compared. Our results showed that the survival time in the early PCI group was significantly prolonged and the survival rate was considerably increased during 3 years. Left ventricular ejection fraction in the early PCI group markedly increased and left ventricular end-diastolic diameter and pro-BNP level decreased significantly. The occurrence rates of perioperative complications in the early PCI group and major adverse cardiac events (MACE) during the follow-up period were significantly reduced. Quality of life scores in the early PCI group markedly improved. We concluded that in patients with coronary heart disease complicated with cardiac insufficiency, early PCI treatment was safe and effective.

Revascularization for Advanced Coronary Artery Disease in Type 2 Diabetic Patients: Choosing Wisely Between PCI and Surgery.[Pubmed:28374179]

Curr Cardiol Rep. 2017 May;19(5):37.

PURPOSE OF REVIEW: Patients with type 2 diabetes mellitus (T2DM) are at an increased risk of systemic atherosclerosis and advanced coronary artery disease (CAD). Herein, we review clinical trials comparing surgical to percutaneous revascularization in the context of the unique pathophysiology in this patient population, and seek to answer the question of optimal strategy of revascularization. RECENT FINDINGS: Early studies showed a signal towards benefit of surgical revascularization over percutaneous revascularization in this group, but there was a paucity of randomized clinical trials (RCT) to directly support this finding. The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM), a large-scale international RCT, was then undertaken and established the benefit of coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) in terms of mortality, myocardial infarction and repeat revascularization; CABG was inferior to PCI with regards to stroke. The quality of life and cost effectiveness also demonstrated a long-term benefit for surgery. The decision as to choice of mode of revascularization in patients with T2DM and advanced CAD depends upon a multitude of factors, including the coronary anatomy, co-morbidities and the patient's surgical risk. These factors influence the recommendation of the cardiovascular team, which should result in a balanced presentation of the short and long-term risks and benefits of either mode of revascularization to the patient and his/her family.

Active site profiling reveals coupling between domains in SRC-family kinases.[Pubmed:23143416]

Nat Chem Biol. 2013 Jan;9(1):43-50.

Protein kinases, key regulators of intracellular signal transduction, have emerged as an important class of drug targets. Chemical proteomic tools that facilitate the functional interrogation of protein kinase active sites are powerful reagents for studying the regulation of this large enzyme family and performing inhibitor selectivity screens. Here we describe a new crosslinking strategy that enables rapid and quantitative profiling of protein kinase active sites in lysates and live cells. Applying this methodology to the SRC-family kinases (SFKs) SRC and HCK led to the identification of a series of conformation-specific, ATP-competitive inhibitors that have a distinct preference for the autoinhibited forms of these kinases. Furthermore, we show that ligands that have this selectivity are able to modulate the ability of the regulatory domains of SRC and HCK to engage in intermolecular binding interactions. These studies provide insight into the regulation of this important family of tyrosine kinases.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.[Pubmed:20615965]

Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80.

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.