936563-96-1

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• Bruton tyrosine kinase (BTK) inhibitor

  Ibrutinib[936563-96-1] is a Bruton's tyrosine kinase (BTK) inhibitor used for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). MCL and CLL are both B-cell non-Hodgkin lymphomas, characterized by treatment resistance and high rate of relapse. Conventional chemotherapy and immunotherapy lack specificity and often result in grade 3 or 4 adverse reactions. Ibrutinib selectively binds to BTK, an essential component for B lymphocyte formation, differentiation, signaling, and survival, irreversibly inhibiting its activity. It effectively inhibits tumor cell proliferation and survival. Additionally, it is rapidly absorbed after oral administration, reaching peak blood concentration in 1-2 hours, and adverse reactions are usually grade 1 or 2. Ibrutinib will become a new treatment option for CLL and MCL.
  On November 13, 2013, the US Food and Drug Administration (FDA) accelerated the approval of Imbruvica (generic name: Ibrutinib) manufactured by Pharmacyclics and Johnson & Johnson for the treatment of a rare aggressive blood cancer called mantle cell lymphoma (MCL). Ibrutinib is an orally available Bruton's tyrosine kinase (BTK) inhibitor, which is a first-in-class innovative drug. It was granted breakthrough therapy designation by the FDA in February 2013 and approved for the treatment of MCL and chronic lymphocytic leukemia (CLL) on November 13, 2013, and February 12, 2014, respectively. This drug selectively and irreversibly inhibits BTK by covalently binding to the active site cysteine residue (Cys-481) of the target protein Btk, effectively preventing the tumor from migrating from B cells to lymphoid tissues that are conducive to tumor growth.
  Information was collated by Xiaonan editor of Chemicalbook.;

• Research and development process

  Ibrutinib(936563-96-1) was developed by American Celera Genentech (Celera Genomics) that was well known because it was the first one drawn "human genome". Pan Zhengying (now Beijing University Shenzhen Graduate School Distinguished Fellow) as the first author of this research and published the process of Ibrutinib in 2007 (ChemMedChem 2 (1): 58-61). But Celera had transferred the development rights to Pharmacyclics Company of California due to funding and resources. Although Pharmacyclics Company was in a very difficult stage, only $ 0.64 for the stock, facing delisting and bankruptcy in that time, company's management has managed to raise funds, spent only $ 2 million to down payment, 100 million shares and future sales royalty and milestone payment of royalties more to get Ibrutinib. In 2011, Johnson & Johnson subsidiary Janssen pay $ 150 million upfront payment in order to get the right to cooperate with Pharmacyclics. Once the new drugs in clinical trials and approved to listing, Pharmacyclics company will get $ 975 million in total revenue, and they will share the sales.When the deal was announced, Pharmacyclics stock is only $ 12. Market value was only several hundred million dollars. However, the stock is already $ 123, $ 9.05 billion value now. ;

• Mechanism

  Signaling pathway of B cell antigen receptor (BCR) is a key driver of tumor growth and spread. BTK as an indispensable participant for BCR signal peptide, it is very important for formation, differentiation, messaging and survival of B lymphocyte. BTK is an identifiable signal peptide molecules of BCR channel. When the signal peptide molecules across the B lymphocyte surface receptors, required channel is activated for transportation, chemotaxis and adhesion, which provide a convenience to be B-cell malignancies.
  Ibrutinib is a small molecule can selectively and covalently bound to a cysteine residue (Cys-481) BTK active site, and irreversibly inhibit BTK activity, thereby inhibiting BCR activated signaling pathway, which could effectively prevent the tumor from B cells to lymphoid tissues where suitable for tumor growth, to reduce B cell proliferation and induce apoptosis of malignant cells, which play a role in the treatment of CLL and MCL. Non-clinical studies have shown that Ibrutinib can inhibit malignant B lymphocyte proliferation and survival. ;

• Metabolism and Elimination

  Ibrutinib(936563-96-1) primarily metabolized by the cytochrome P450 (CYP3A and a small part of the CYP2D6) and produce a variety of metabolites after metabolism. The metabolite (PCI-45227) is a kind of dihydrodiol substance which is an activity of inhibiting BTK.Compared with Ibrutinib, PCI-45227 has much stronger inhibition on BTK, which is about 15 times stronger. At steady state, the average rate of metabolism of PCI-45227 is around 1~2.8.
  Apparent clearance (CL/F) of Ibrutinibis is approximately 1 000 L/h, the half-life (t1/2) is 4~6 h. Ibrutinib mainly be metabolites in the body, excrete with the feces. To healthy subjects by oral radioactive 14C-labeled Ibrutinib, found that nearly 90% of the radiation were eliminated in 168 h, most (about 80%) of them were excreted with the feces, and nearly 10% were excreted in the urine, about 1 % be prototypes were excreted with the feces.
  Elimination of Ibrutinib will not make a difference in age (37 to 84 years) and gender, but systemic exposure of patients with moderate hepatic injury will be 6 times higher than in healthy subjects. ;

• Patents

  Foreign patents: WO 2008039218 (compound); WO 2013003629 (purposes)
  US Patent Number: 7,514,444, 7,718,662, patents is valid: December 2026
  Domestic patent: CN101610676A, CN101610676B, CN101805341A, CN101805341B, CN102746305A, CN102887900A ;

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