Atirmociclib
Atirmociclib is an investigational orally bioavailable and CDK4-specific inhibitor being developed by Pfizer for the treatment of various solid tumors, particularly hormone receptor-positive, HER2-negative breast cancer. The safety and efficacy of atirmociclib have not been established, as it remains in clinical development as of September 2025.
Mechanism of action
Atirmociclib is designed as a CDK4-specific inhibitor, distinguishing it from dual CDK4/6 inhibitors currently approved for cancer treatment. The drug targets cyclin-dependent kinase 4, which plays a role in cell cycle regulation.Atirmociclib functions as a selective inhibitor of the CDK4/cyclin D complex, which plays a crucial role in cell cycle regulation. The drug works by targeting the CDK4 kinase, rendering the retinoblastoma /E2F transcription system inactive, which ultimately leads to cell cycle arrest in the G1 phase. This mechanism is particularly effective in tumors that have lost Rb cell cycle-suppressive function, a common feature in various solid tumors.
The selective nature of atirmociclib represents a significant advancement over existing dual CDK4/6 inhibitors. By specifically targeting CDK4 while limiting CDK6 inhibition, atirmociclib is designed to maintain antitumor efficacy while potentially reducing dose-limiting hematologic toxicities, particularly neutropenia, which is believed to be primarily driven by CDK6 inhibition.
Clinical development
Atirmociclib is currently being evaluated in clinical trials for the treatment of advanced solid tumors. Clinical studies are ongoing with estimated completion dates extending to 2027–2028, reflecting the early stage of development for this investigational compound.Preclinical research published in Cancer Cell in March 2025 reported atirmociclib as a next-generation CDK4-selective inhibitor with enhanced anti-tumor activity and reduced predicted toxicity compared to FDA-approved dual CDK4/6 inhibitors, though these findings require validation in clinical studies.
Preclinical studies
Preclinical research has demonstrated that atirmociclib exhibits enhanced anti-tumor activity compared to FDA-approved dual CDK4/6 inhibitors while showing reduced predicted toxicity. Studies have shown that CDK4-selective inhibition can provide improved preclinical anti-tumor efficacy and safety profiles compared to dual CDK4/6 inhibition strategies.The preclinical development program has explored combination approaches with various therapeutic modalities, including endocrine therapy, CDK2 inhibition, HER2 antibodies, and immune checkpoint inhibitors. These combination strategies are designed to counter resistance mechanisms to CDK4 inhibition and expand the potential therapeutic applications of cell cycle targeting therapy.
Clinical trials
Atirmociclib has entered clinical development as part of Pfizer's extensive oncology pipeline. The clinical program is evaluating atirmociclib both as a single agent and in combination with other therapeutic approaches, particularly focusing on patients with hormone receptor-positive, HER2-negative breast cancer.Early clinical studies have included heavily pretreated patient populations, including those who have previously received CDK4/6 inhibitor therapy. This approach allows for the evaluation of atirmociclib's potential to overcome resistance to existing CDK4/6 inhibitors and provide therapeutic benefit in patients with limited treatment options.
Safety profile and toxicity
One of the key differentiating features of atirmociclib is its potential for improved safety profile compared to existing dual CDK4/6 inhibitors. The selective targeting of CDK4 while limiting CDK6 inhibition is specifically designed to reduce neutropenia, the most common dose-limiting toxicity associated with current CDK4/6 inhibitors.The rationale for this approach is based on preclinical evidence suggesting that neutropenia is primarily driven by CDK6 inhibition rather than CDK4 inhibition. By selectively targeting CDK4, atirmociclib aims to maintain therapeutic efficacy while potentially allowing for higher or more sustained dosing without the dose-limiting hematologic toxicities that can compromise treatment outcomes with existing agents.