Dasatinib
[CAS# 302962-49-8]

Identification

• Classification: API >> Antineoplastic agents >> Tinic antineoplastic agents
• Name: Dasatinib
• Synonyms: BMS 354825; N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide
• Molecular Formula: C₂₂H₂₆ClN₇O₂S
• Molecular Weight: 488.01
• CAS Registry Number: 302962-49-8
• EC Number: 801-607-0
• SMILES: CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)CCO

Properties

• Solubility: DMSO 125mg/mL, Water $lessThan$1.2mg/mL, Ethanol $lessThan$1.2mg/mL (Expl.)

Safety Data

• Hazard Symbols: GHS06;GHS08;GHS09 Danger
• Risk Statements: H300-H351-H360-H372-H400-H410
• Safety Statements: P203-P260-P264-P270-P273-P280-P301+P316-P318-P319-P321-P330-P391-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Reproductive toxicity	Repr.	2	H361
Carcinogenicity	Carc.	2	H351
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Skin irritation	Skin Irrit.	2	H315
Serious eye damage	Eye Dam.	1	H318
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Specific target organ toxicity - single exposure	STOT SE	2	H371
Reproductive toxicity	Repr.	1B	H360
Reproductive toxicity	Lact.	-	H362
Reproductive toxicity	Repr.	1B	H360Df
Reproductive toxicity	Repr.	1A	H360
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Acute toxicity	Acute Tox.	2	H300
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

Dasatinib is a potent, orally active tyrosine kinase inhibitor used primarily in the treatment of certain types of cancer, particularly chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It was developed as a treatment for cancers that are driven by abnormal tyrosine kinase activity, which leads to uncontrolled cell growth.

The discovery of dasatinib was driven by the need for more effective treatments for CML, a form of leukemia that is characterized by the presence of the Philadelphia chromosome, which results in the creation of the BCR-ABL fusion protein. This protein is a constitutively active tyrosine kinase that promotes abnormal cell growth. Traditional treatments for CML, such as interferon therapy, were often less effective or came with significant side effects. Dasatinib was developed as a second-generation tyrosine kinase inhibitor with the goal of targeting the BCR-ABL fusion protein more efficiently and with fewer side effects than earlier treatments.

Dasatinib works by binding to the ATP-binding site of the BCR-ABL fusion protein, preventing its activation. It is able to target both the active and inactive forms of the protein, which is important because CML can develop resistance to drugs that only target the active form. This broad-spectrum inhibition makes dasatinib a more potent and effective treatment compared to earlier drugs, such as imatinib.

Beyond CML, dasatinib has also shown efficacy in treating other cancers with similar tyrosine kinase-driven mutations. It has been used in the treatment of Ph+ ALL and has been studied in other cancers like non-small cell lung cancer (NSCLC) and certain types of solid tumors, where the inhibition of various tyrosine kinases can help slow tumor progression.

The approval of dasatinib by the U.S. Food and Drug Administration (FDA) came in 2006 for the treatment of Ph+ CML and Ph+ ALL, marking a significant advancement in the treatment options for patients with these types of leukemia. Since its approval, dasatinib has become a cornerstone of therapy for these diseases, especially for patients who are resistant or intolerant to imatinib, the first-line treatment.

In addition to its primary use in hematological malignancies, dasatinib is being studied in combination with other drugs and in various clinical trials for its potential in treating a broader range of cancers, including solid tumors. Ongoing research aims to understand the full spectrum of its activity, optimize treatment regimens, and overcome resistance mechanisms that can develop with prolonged use.

Dasatinib is generally well-tolerated, although it can cause side effects such as fluid retention, gastrointestinal issues, and, in some cases, myelosuppression (decreased bone marrow activity). Because of its potency and ability to target multiple tyrosine kinases, it is important for patients to be monitored closely while on dasatinib therapy to manage any adverse effects and adjust the dose as necessary.

In conclusion, dasatinib is a highly effective tyrosine kinase inhibitor that has revolutionized the treatment of Philadelphia chromosome-positive leukemias, particularly CML and Ph+ ALL. Its ability to target the BCR-ABL fusion protein and other tyrosine kinases has made it a valuable tool in the treatment of these cancers. As research continues, its potential use in other cancers and in combination therapies holds promise for expanding its therapeutic applications.

References

2007. Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Cancer Chemotherapy and Pharmacology, 61(3).
DOI: 10.1007/s00280-007-0478-8

2007. Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Molecular Cancer Therapeutics, 6(4).
DOI: 10.1158/1535-7163.mct-06-0446

2024. Impact of Dasatinib on Female Reproductive Health in Philadelphia-Positive Leukemia Patients. Indian Journal of Hematology and Blood Transfusion.
DOI: 10.1007/s12288-024-01932-6