Atirmociclib

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Atirmociclib

CAS 2380321-51-5

MF C22H27ClFN5O3,
463.9 g/mol

(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

(3S,4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan2-yl)-1H-1,3-benzimidazol-6-yl]pyrimidin-2-yl}amino)oxan-3-ol

 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxpropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

D-threo-Pentitol, 1,5-anhydro-3-[[5-chloro-4-[4-fluoro-2-(1-hydroxy-1-methylethyl)-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinyl]amino]-2,3-dideoxy-
cyclin-dependent kinase (CDK) inhibitor, antineoplastic, PF 07220060, S743GOJ5LJ, CDK4/6-IN-6

Atirmociclib is an orally bioavailable inhibitor of cyclin-dependent kinase 4 (CDK4), with potential antineoplastic activity. Upon administration, atirmociclib selectively inhibits CDK4, which inhibits the phosphorylation of retinoblastoma protein (Rb) early in the G1 phase, prevents CDK-mediated G1-S-phase transition and leads to cell cycle arrest. This suppresses DNA replication and inhibits tumor cell proliferation. CDK4, a serine/threonine kinase, is upregulated in many tumor cell types and plays a key role in the regulation of both cell cycle progression from the G1-phase into the S-phase and tumor cell proliferation.

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]

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c02137

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481329&_cid=P22-MK0K3I-13424-1

Example A94 (Scheme A-15): Preparation of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94)

      A 2 L three-neck round bottom flask was charged with 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-23) (112 g, 292 mmol), 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol hydrochloride (51.6 g, 336 mmol), and MeCN (1.1 L). DIPEA (132 g, 1.02 mol, 178 mL) was added at room temperature. The reaction mixture was heated to 80° C. (internal temperature) and stirred at the same temperature for 40 h to provide a brown solution. LCMS analysis showed remaining starting material. Additional 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol hydrochloride (6.73 g, 43.8 mmol) was added at 80° C. (internal temperature) and the reaction was stirred at 80° C. (internal temperature) for an additional 10 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was taken up in 1:1 EtOAc/H 2O (1.5 L). Some solids were precipitated. EtOH (100 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with H 2O (2×300 mL), dried over Na 2SO 4, and filtered. To the filtrate was added sulfhydryl silica gel (Accela, 8 g, 0.7-1.4 mmol/g). The resulting mixture was stirred at room temperature for 1 h and then filtered through a pad of Celite. Treatment with sulfhydryl silica gel was repeated in identical fashion and the filtrate was concentrated to dryness. The crude residue was slurried in MeCN (500 mL) at room temperature for 16 h. The suspension was filtered and the filter cake was washed with MeCN (2×100 mL). The filter cake was slurried again with MeCN (300 mL) at room temperature for 6 h. The mixture was filtered and the filter cake was washed with MeCN (2×100 mL). The filter cake was collected and dried under vacuum and then dried in a drying oven (45° C. for 20 h, 50° C. for 64 h) to provide 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxpropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94) (90 g, 66% yield) as a white solid. 1H NMR (400 MHz, 80° C., DMSO-d 6) δ 8.38 (s, 1H), 8.00 (s, 1H), 7.43 (d, J=11.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 5.80 (hept, J=7.0 Hz, 1H), 5.56 (s, 1H), 4.71 (d, J=5.3 Hz, 1H), 3.91-3.79 (m, 3H), 3.61-3.52 (m, 1H), 3.41-3.31 (m, 1H), 3.12-3.07 (m, 1H), 2.09-2.00 (m, 1H), 1.70 (s, 6H), 1.67-1.52 (m, 7H); 19F NMR (377 MHz, CDCl 3) δ −127.2; m/z (ESI+) for (C 22H 27ClFN 6O 3), 464.2 (M+H) +; [α] D 22=−12.6 (c=0.2, MeOH).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481329&_cid=P22-MK0KHW-23947-1

PAT

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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]

References

  1.  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.  “Pfizer Pipeline”. Pfizer.
  5.  “Atirmociclib PF-07220060”. Pfizer Oncology Development. Retrieved 3 September 2025.
  6.  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.  “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.  “Pfizer dials down its atirmociclib ambitions”. ApexOnco. 1 May 2025.
Identifiers
IUPAC name
CAS Number2380321-51-5
PubChem CID146219790
ChemSpider115009592
UNIIS743GOJ5LJ
KEGGD12834
ChEMBLChEMBL5187755
Chemical and physical data
FormulaC22H27ClFN5O3
Molar mass463.94 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

///////////Atirmociclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, PF 07220060, S743GOJ5LJ, CDK4/6-IN-6

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