Atirmociclib

Atirmociclib
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
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

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

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

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

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

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

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

References

  1. ^ a b c d Pfizer (2 February 2025). A Phase 1/2A Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of Pf-07220060 as a Single Agent and as Part of Combination Therapy in Participants With Advanced Solid Tumors (Report). clinicaltrials.gov.
  2. ^ Shapiro GI (March 2017). "The evolving role of cyclin-dependent kinase inhibitors in cancer management". Clinical Advances in Hematology & Oncology. 15 (3): 174–177. PMID 28398270.
  3. ^ "CDK4 inhibitor PF-07220060". www.cancer.gov. 2 February 2011. Retrieved 3 September 2025.
  4. ^ a b c "Pfizer Pipeline". Pfizer.
  5. ^ a b c d "Atirmociclib PF-07220060". Pfizer Oncology Development. Retrieved 3 September 2025.
  6. ^ a b c d e f g Chang J, Lu J, Liu Q, Xiang T, Zhang S, Yi Y, et al. (March 2025). "Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis". Cancer Cell. 43 (3): 380–397.e7. doi:10.1016/j.ccell.2025.02.009. PMID 40068596.
  7. ^ Topacio BR, Zatulovskiy E, Cristea S, Xie S, Tambo CS, Rubin SM, et al. (May 2019). "Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix". Molecular Cell. 74 (4): 758–770.e4. doi:10.1016/j.molcel.2019.03.020. PMC 6800134. PMID 30982746.
  8. ^ Helsten T, Kato S, Schwaederle M, Tomson BN, Buys TP, Elkin SK, et al. (July 2016). "Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics". Molecular Cancer Therapeutics. 15 (7): 1682–1690. doi:10.1158/1535-7163.MCT-16-0071. PMID 27196769.
  9. ^ a b c d "ESMO 2024 – combos could be the way forward for CDK2". ApexOnco. 15 September 2024.
  10. ^ Palmer CL, Boras B, Pascual B, Li N, Li D, Garza S, et al. (March 2025). "CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety". Cancer Cell. 43 (3): 464–481.e14. doi:10.1016/j.ccell.2025.02.006. PMID 40068598.
  11. ^ "Pfizer Highlights Diverse Oncology Portfolio and Combination Approaches at ESMO 2024". Pfizer. 2024.
  12. ^ Pfizer (12 August 2025). A Phase 1/2a Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetic, Pharmacodynamic, and Anti-Tumor Activity of Pf-07248144 in Participants With Advanced or Metastatic Solid Tumors (Report). clinicaltrials.gov.
  13. ^ Pfizer (2 July 2025). An Interventional Safety and Efficacy Phase 1/2, Open-Label Study to Investigate Tolerability, Pk, and Antitumor Activity of Vepdegestrant (Arv-47/Pf-07850327), an Oral Proteolysis Targeting Chimera, in Combination With Pf-07220060 in Participants Aged 18 Years and Older With Er+/her2- Advanced or Metastatic Breast Cancer (Report). clinicaltrials.gov.
  14. ^ Pfizer (14 November 2024). A Phase 1/2, Open-Label, Multicenter, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of PF-07220060 in Combination With Pf-07104091 Plus Endocrine Therapy in Participants With Advanced Solid Tumors (Report). clinicaltrials.gov.
  15. ^ Pfizer (17 June 2025). (FOURLIGHT-3) (Report). clinicaltrials.gov.
  16. ^ Pfizer (13 March 2025). An Interventional, Open-Label, Randomized, Multicenter Phase 3 Study of PF-07220060 Plus Letrozole Compared to cdk4/6 Inhibitor Plus Letrozole in Participants Over 18 Years of Age With Hormone Receptor (Hr)-Positive, her2-Negative Advanced/Metastatic Breast Cancer Who Have Not Received Any Prior Systemic Anticancer Treatment for Advanced/Metastatic Disease (FOURLIGHT-1) (Report). clinicaltrials.gov.
  17. ^ Pfizer (15 November 2024). An Interventional, Open-Label, Randomized, Multicenter, Phase 2 Study of Pf-07220060 Plus Letrozole Compared to Letrozole Alone in Postmenopausal Women 18 Years or Older With Hormone Receptor-Positive, her2-Negative Breast Cancer in the Neoadjuvant Setting (Report). clinicaltrials.gov.
  18. ^ a b c "Pfizer dials down its atirmociclib ambitions". ApexOnco. 1 May 2025.
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