Capivasertib
[CAS# 1143532-39-1]

Identification

• Classification: Biochemical >> Inhibitor >> PI3K/Akt/mTOR inhibitor (PI3K/Akt/mTOR) >> Akt inhibitor
• Name: Capivasertib
• Synonyms: 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinecarboxamide
• Molecular Formula: C₂₁H₂₅ClN₆O₂
• Molecular Weight: 428.92
• CAS Registry Number: 1143532-39-1
• EC Number: 682-662-6
• SMILES: C1CN(CCC1(C(=O)N[C@@H](CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4

Properties

• Solubility: 86 mg/mL (DMSO), <1 mg/mL (water), <1 mg/mL (ethanol)
• Density: 1.381±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.670, Calc.^*

Safety Data

• Hazard Symbols: GHS07;GHS08 Warning
• Risk Statements: H302-H373
• Safety Statements: P260-P264-P270-P273-P301+P317-P319-P330-P391-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - repeated exposure	STOT RE	2	H373

Discovery and Applications

Capivasertib is an orally bioavailable, selective inhibitor of the serine/threonine kinase AKT, a key component of the PI3K/AKT signaling pathway, which is frequently dysregulated in various cancers. This pathway plays a significant role in cell proliferation, survival, and metabolism, making it an attractive target for anticancer therapy. Capivasertib binds to and inhibits all three isoforms of AKT (AKT1, AKT2, and AKT3), thereby preventing the phosphorylation of downstream targets involved in tumorigenesis. The inhibition of AKT disrupts cellular survival mechanisms, sensitizing cancer cells to apoptosis and reducing tumor growth.

Capivasertib was discovered and developed by AstraZeneca as part of efforts to create targeted therapies for cancers driven by abnormalities in the PI3K/AKT/mTOR pathway. The compound emerged from a structure-based drug design program aimed at producing ATP-competitive inhibitors with high specificity for AKT over other kinases. Its design incorporates structural features that enhance binding affinity to the ATP-binding pocket of AKT, resulting in potent inhibition.

The synthesis of capivasertib involves the construction of a pyrrolo[2,3-d]pyrimidine core, a scaffold commonly used in kinase inhibitors. This core is functionalized with various substituents that improve its pharmacokinetic properties and selectivity for AKT. The synthetic route includes sequential cyclization and coupling steps, resulting in a highly efficient and reproducible process suitable for large-scale production.

Capivasertib has demonstrated significant antitumor activity in preclinical models and clinical trials, particularly in cancers harboring mutations or amplifications in PIK3CA, PTEN loss, or AKT mutations. Clinical trials have shown promising results in patients with breast cancer, prostate cancer, and other solid tumors. In combination with other anticancer agents, such as paclitaxel or fulvestrant, capivasertib has been shown to overcome resistance mechanisms associated with endocrine therapies and chemotherapy.

Capivasertib’s role in cancer treatment continues to expand as ongoing studies explore its application in various cancer types and combination regimens. Its ability to target a critical node in cancer signaling underscores its potential as a valuable therapeutic option for patients with advanced or treatment-resistant malignancies.

References

2013. Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases. Journal of Medicinal Chemistry, 56(5).
DOI: 10.1021/jm301762v

2013. The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere. Journal of Translational Medicine, 11.
DOI: 10.1186/1479-5876-11-241

2024. Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial. The Lancet. Oncology, 25(9).
DOI: 10.1016/s1470-2045(24)00373-5