Atirmociclib

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Atirmociclib
File:Atirmociclib.svg
Identifiers
  • (3S,4R)-4-[[5-chloro-4-[7-fluoro-2-(2-hydroxypropan-2-yl)-3-propan-2-ylbenzimidazol-5-yl]pyrimidin-2-yl]amino]oxan-3-ol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
  • {{#property:P3117}}Lua error in Module:EditAtWikidata at line 29: attempt to index field 'wikibase' (a nil value).
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 29: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC22H27ClFN5O3
Molar mass463.94 g·mol−1
3D model (JSmol)
  • CC(C)N1C2=C(C(=CC(=C2)C3=NC(=NC=C3Cl)N[C@@H]4CCOC[C@H]4O)F)N=C1C(C)(C)O
  • InChI=1S/C22H27ClFN5O3/c1-11(2)29-16-8-12(7-14(24)19(16)27-20(29)22(3,4)31)18-13(23)9-25-21(28-18)26-15-5-6-32-10-17(15)30/h7-9,11,15,17,30-31H,5-6,10H2,1-4H3,(H,25,26,28)/t15-,17-/m1/s1
  • Key:QYJLBHRAPDJOSO-NVXWUHKLSA-N

Atirmociclib (development code PF-07220060) 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.[1][2] The safety and efficacy of atirmociclib have not been established, as it remains in clinical development as of September 2025.[3][4][5]

Mechanism of action

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Atirmociclib is designed as a CDK4-specific inhibitor, distinguishing it from dual CDK4/6 inhibitors currently approved for cancer treatment.[6] The drug targets cyclin-dependent kinase 4, which plays a role in cell cycle regulation.[1][7][8]

Atirmociclib functions as a selective inhibitor of the CDK4/cyclin D complex, which plays a crucial role in cell cycle regulation.[4] The drug works by targeting the CDK4 kinase, rendering the retinoblastoma (Rb)/E2F transcription system inactive, which ultimately leads to cell cycle arrest in the G1 phase.[4] This mechanism is particularly effective in tumors that have lost Rb cell cycle-suppressive function, a common feature in various solid tumors.[5]

The selective nature of atirmociclib represents a significant advancement over existing dual CDK4/6 inhibitors.[6] 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.[9]

Clinical development

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Atirmociclib is currently being evaluated in clinical trials for the treatment of advanced solid tumors.[1] Clinical studies are ongoing with estimated completion dates extending to 2027–2028, reflecting the early stage of development for this investigational compound.[1]

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.[6]

Preclinical studies

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Preclinical research has demonstrated that atirmociclib exhibits enhanced anti-tumor activity compared to FDA-approved dual CDK4/6 inhibitors while showing reduced predicted toxicity.[6] Studies have shown that CDK4-selective inhibition can provide improved preclinical anti-tumor efficacy and safety profiles compared to dual CDK4/6 inhibition strategies.[10]

The preclinical development program has explored combination approaches with various therapeutic modalities, including endocrine therapy, CDK2 inhibition, HER2 antibodies, and immune checkpoint inhibitors.[6] These combination strategies are designed to counter resistance mechanisms to CDK4 inhibition and expand the potential therapeutic applications of cell cycle targeting therapy.[6]

Clinical trials

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Atirmociclib has entered clinical development as part of Pfizer's extensive oncology pipeline.[11] 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.[9][12][13][14][15][16][17]

Early clinical studies have included heavily pretreated patient populations, including those who have previously received CDK4/6 inhibitor therapy.[9] 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.[9]

Safety profile and toxicity

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One of the key differentiating features of atirmociclib is its potential for improved safety profile compared to existing dual CDK4/6 inhibitors.[6] 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.[18]

The rationale for this approach is based on preclinical evidence suggesting that neutropenia is primarily driven by CDK6 inhibition rather than CDK4 inhibition.[18] 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.[18]

Regulatory status

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As of September 2025, atirmociclib remains an investigational drug that has not received approval from the FDA or other regulatory agencies.[5] The compound is part of Pfizer's oncology development pipeline.[5]

See also

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References

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