Atirmociclib

Last updated

Atirmociclib
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
Chemical and physical data
Formula C22H27ClFN5O3
Molar mass 463.94 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]

Contents

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. 1 2 3 4 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 (1 March 2017). "The evolving role of cyclin-dependent kinase inhibitors in cancer management". Clinical Advances in Hematology & Oncology: H&O. 15 (3): 174–177. ISSN   1543-0790. PMID   28398270.
  3. ↑ "CDK4 inhibitor PF-07220060". www.cancer.gov. 2 February 2011. Retrieved 3 September 2025.
  4. 1 2 3 "Pfizer Pipeline". Pfizer.
  5. 1 2 3 4 "Atirmociclib PF-07220060". Pfizer Oncology Development. Retrieved 3 September 2025.
  6. 1 2 3 4 5 6 7 Chang J, Lu J, Liu Q, Xiang T, Zhang S, Yi Y, et al. (10 March 2025). "CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety". 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. (16 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. ISSN   1097-4164. PMC   6800134 . PMID   30982746.
  8. ↑ Helsten T, Kato S, Schwaederle M, Tomson BN, Buys TP, Elkin SK, et al. (1 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. ISSN   1538-8514. PMID   27196769.
  9. 1 2 3 4 "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. (10 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.{{cite journal}}: CS1 maint: overridden setting (link)
  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 1B/2, OPEN-LABEL STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF VEPDEGESTRANT (ARV-471/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 1B/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). 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-3) (Report). clinicaltrials.gov.
  16. ↑ Pfizer (13 March 2025). AN INTERVENTIONAL, OPEN-LABEL, RANDOMIZED, MULTICENTER PHASE 2 STUDY OF PF-07220060 PLUS FULVESTRANT COMPARED TO INVESTIGATOR'S CHOICE OF THERAPY IN PARTICIPANTS AT LEAST 18 YEARS OF AGE WITH HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED/METASTATIC BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR CDK 4/6 INHIBITOR-BASED THERAPY (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. 1 2 3 "Pfizer dials down its atirmociclib ambitions". ApexOnco. 1 May 2025.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.