Ibrutinib
[CAS 936563-96-1]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: Ibrutinib
• Synonyms: 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one
• Molecular Formula: C₂₅H₂₄N₆O₂
• Molecular Weight: 440.50
• CAS Registry Number: 936563-96-1
• EC Number: 805-642-2
• SMILES: C=CC(=O)N1CCC[C@H](C1)N2C3=NC=NC(=C3C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)N

Properties

• Density: 1.3$+/-$0.1 g/cm³ Calc.^*
• Boiling point: 715.0$+/-$60.0 $degree$C 760 mmHg (Calc.)^*
• Flash point: 386.2$+/-$32.9 $degree$C (Calc.)^*
• Solubility: 10 mM in DMSO (Expl.)
• Index of refraction: 1.696 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08;GHS09 Danger
• Risk Statements: H302-H315-H319-H335-H351-H360-H373-H410
• Safety Statements: P203-P260-P261-P264-P264+P265-P270-P271-P273-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P318-P319-P321-P330-P332+P317-P337+P317-P362+P364-P391-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	1B	H360
Specific target organ toxicity - single exposure	STOT SE	3	H335
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Reproductive toxicity	Repr.	2	H361d
Carcinogenicity	Carc.	2	H351

Discovery and Applications

Ibrutinib is a small-molecule anticancer drug that belongs to the class of Bruton's tyrosine kinase (BTK) inhibitors. It is used primarily in the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia, and certain other B-cell lymphomas.

The chemical structure of ibrutinib is based on a substituted heteroaromatic scaffold containing an acrylamide electrophilic group. This acrylamide moiety is a key functional feature that enables covalent binding to its target enzyme. The molecule was designed through structure-based drug design to selectively inhibit BTK, a critical signaling kinase in B-cell receptor (BCR) signaling pathways.

Ibrutinib acts as an irreversible inhibitor of Bruton's tyrosine kinase. It forms a covalent bond with a specific cysteine residue (Cys481) in the active site of BTK. This irreversible binding permanently inactivates the enzyme in affected cells until new BTK protein is synthesized. BTK plays an essential role in transmitting signals from the B-cell receptor, which regulate B-cell activation, proliferation, and survival.

By inhibiting BTK, ibrutinib disrupts downstream signaling pathways such as NF-κB, MAPK, and PI3K/AKT. This leads to reduced proliferation and survival of malignant B cells and can induce apoptosis or inhibit migration and adhesion of cancer cells within lymphoid tissues. These effects contribute to tumor regression and disease control in B-cell malignancies.

Ibrutinib was developed as part of a new generation of targeted cancer therapies aimed at interfering with specific intracellular signaling pathways rather than broadly cytotoxic mechanisms. Its discovery marked a major advancement in the treatment of hematologic cancers by targeting a kinase that is largely restricted to B cells and certain immune cells.

After oral administration, ibrutinib is rapidly absorbed and extensively metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4). Its pharmacokinetic profile supports once-daily dosing. The drug exhibits high tissue distribution, particularly in lymphoid tissues where malignant B cells reside.

Clinically, ibrutinib is used as a long-term oral therapy for patients with various B-cell malignancies. It can be used as monotherapy or in combination with other agents depending on the disease type and treatment protocol. Its use has significantly improved progression-free survival in several lymphoid cancers compared with older chemotherapeutic approaches.

Adverse effects associated with ibrutinib include bleeding risk due to effects on platelet signaling, atrial fibrillation, diarrhea, fatigue, musculoskeletal pain, and increased susceptibility to infections. These effects are related to both its on-target BTK inhibition in immune cells and off-target kinase interactions.

From a medicinal chemistry perspective, the acrylamide group in ibrutinib is essential for its covalent mechanism of action. This electrophilic moiety undergoes Michael addition with the thiol group of the target cysteine residue in BTK, forming a stable covalent bond. This irreversible inhibition contributes to its prolonged pharmacodynamic effect despite relatively short plasma half-life.

Overall, ibrutinib is an orally active, covalent Bruton's tyrosine kinase inhibitor that blocks B-cell receptor signaling. By irreversibly inhibiting BTK, it suppresses malignant B-cell survival and proliferation, making it an important targeted therapy in the treatment of several B-cell lymphoproliferative disorders.

References

2026. Emerging Therapeutics in Rheumatoid Arthritis. Current Rheumatology Reports.
DOI: 10.1007/s11926-025-01209-5

2026. Dasatinib boosts γδ T cell expansion and memory phenotypes with enhanced antitumor immunity. Cancer immunology, immunotherapy : CII.
DOI: 10.1007/s00262-026-04335-w

2026. Discovery of a novel VEGFR2 inhibitor using integrated structure-based docking study and functional validation: potential applications in targeted cancer therapy. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.
DOI: 10.1016/j.jsps.2026.02.001