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Our Science

Our team of prestigious clinical and research professionals is leading new approaches to treating B-cell–mediated conditions, including blood cancers and immune-mediated disorders. We are advancing the field with a pipeline of products that demonstrate vast potential.

By studying promising molecules and, in some cases, working with partners, we are committed to developing and delivering therapies that work harmoniously with the human body and advance the treatment landscape for people living with life-threatening diseases.

Science you can believe in.

Bruton’s Tyrosine Kinase (BTK) Inhibitors

We are pioneering the development of orally dosed inhibitors of Bruton’s tyrosine kinase (BTK). BTK is a signaling protein that is critically important for the development and activity of B cells—immune cells that produce antibodies to help the body fight infection. Abnormal activation of B cells may lead to B-cell malignancies and B-cell–mediated disorders.1-4

Inhibiting B cells by targeting BTK is a novel approach for treating many different human diseases associated with the inappropriate activation of B cells.

How BTK Inhibitors Work

BTK inhibitors work to disable the activation of B cells by disturbing and interrupting the signaling and activation pathways that cause B cells to differentiate and proliferate in the body.5,6

B-cell lymphomas and leukemias (B-cell malignancies) and immune inflammatory diseases occur when mutations alter B cells, causing overactive and uncontrolled growth and activation.3

Our Work with BTK Inhibitors

Ibrutinib was first designed and synthesized at Celera Genomics by Zhengying Pan and a team of biochemists. Dr. Pan’s team used a structure-based approach to design a series of small molecules that inactivated Bruton’s tyrosine kinase by creating a covalent (strong chemical) bond with the protein that blocks its enzymatic activity.7 Ibrutinib, a potent covalent inhibitor, was chosen for further preclinical development based on the discovery of its anti-lymphoma properties. The strong chemical bond created with a target can result in the interruption of a target’s function and interfere with cancer cell proliferation.8

The covalent bond that ibrutinib forms in the active catalytic site of BTK results in inhibition of BTK function. Within four hours of delivery, ibrutinib binds to and inhibits BTK in B cells, and this inhibition is generally maintained for 24 hours.9 

Our scientists have identified specific potential applications for ibrutinib. 

Ibrutinib is being investigated in several disease areas. Areas of study include:

(Ibrutinib is not FDA-approved for all diseases listed below)

B-cell malignancies:

  • Chronic lymphocytic leukemia (CLL)
  • Mantle cell lymphoma (MCL)
  • Diffuse large B-cell lymphoma (DLBCL)
  • Multiple myeloma (MM)
  • Follicular lymphoma (FL)
  • Waldenström’s macroglobulinemia (WM)
  • Marginal zone lymphoma (MZL)
  • Other types of blood cancers

Immunologic disease:

  • Graft-versus-host disease (GVHD)

In November 2013, IMBRUVICA® (ibrutinib) was first approved for use by the US Food and Drug Administration (FDA). That path to approval included receiving three of the first six Breakthrough Therapy Designations from the FDA in efforts to get the medicine to patients in need sooner.

Next Generation BTK Inhibitors

With the vast potential ibrutinib has demonstrated in both clinical and real-world settings, our scientists are actively pursuing pre-clinical and clinical development of next-generation BTK inhibitor compounds specifically designed to address immune-mediated diseases that may be affected by B-cell inhibition.

Learn about BTK inhibitor clinical trials.

References:
  1. Maas A, Hendriks RW. Role of Bruton’s tyrosine kinase in B cell development. Dev Immunol. 2001;8(3-4):171-181.
  2. National Cancer Institute. Definition: B cell. http://www.cancer.gov/dictionary?cdrid=45611. Accessed October 14, 2014.
  3. Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol. 2002;2(12):920-932.
  4. Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6:59. doi: 10.1186/1756-8722-6-59.
  5. de Gorter DJ, Beuling EA, Kersseboom R, et al. Bruton’s tyrosine kinase and phospholipase CƔ2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26(1):93-104.
  6. D’Cruz OJ, Uckun FM. Novel Bruton’s tyrosine kinase inhibitors currently in development. Onco Targets Ther. 2013;6:161-176.
  7. Pan Z, Scheerens H, Li S-J, et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem. 2007;2(1):58-61.
  8. Chang BY, Francesco M, DeRooij MFM, et al. Egress of CD19+CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122(14):2412-2424. doi: 10.1182/blood-2013-02-482125.
  9. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.