Top Qs
Timeline
Chat
Perspective
Tegtociclib
Experimental CDK2-selective inhibitor for hormone receptor-positive breast cancer From Wikipedia, the free encyclopedia
Remove ads
Tegtociclib (development code PF-07104091) is an investigational small molecule drug developed by Pfizer for the treatment of hormone receptor-positive breast cancer.[1] It is a selective inhibitor of cyclin-dependent kinase 2 (CDK2), designed to address resistance mechanisms that emerge in patients treated with CDK4/6 inhibitors.[1]
Tegtociclib represents a novel approach to targeting the cell cycle machinery in cancer, focusing specifically on CDK2 rather than the more broadly targeted CDK4/6 pathway.[2] The drug is currently in Phase 1b/2 clinical development, being evaluated both as monotherapy and in combination with other anticancer agents.[1]
Remove ads
Mechanism of action
Tegtociclib selectively binds to and inhibits the activity of cyclin-dependent kinase 2 (CDK2), a key regulator of cell cycle progression.[1] CDK2 is activated by cyclin E and cyclin A during the G1/S transition and S phase of the cell cycle, respectively, and plays a crucial role in DNA replication and cell division.[1]
The primary mechanism involves CDK2-mediated phosphorylation of the retinoblastoma protein (Rb) and other downstream targets that control cell cycle progression.[1] When CDK2 is inhibited by tegtociclib, Rb remains in its hypophosphorylated state, preventing the release of E2F transcription factors and subsequently blocking the transition from G1 to S phase.[3]
Beyond Rb phosphorylation, CDK2 has been shown to phosphorylate a wide variety of target proteins involved in cancer pathogenesis, DNA repair, and cellular metabolism.[1] This broad range of substrates suggests that CDK2 inhibition may have multiple anticancer effects beyond simple cell cycle arrest.[4]
Remove ads
Rationale for development
The development of tegtociclib addresses a significant clinical challenge in the treatment of hormone receptor-positive breast cancer: resistance to CDK4/6 inhibitors.[1] While CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib have revolutionized the treatment of HR-positive breast cancer, both primary and secondary resistance represent major clinical challenges.[5]
Research has identified several resistance mechanisms to CDK4/6 inhibition, including upregulation of CDK2 activity through increased cyclin E expression, loss of Rb protein function, and activation of alternative cell cycle pathways.[5] Since CDK2 activity is largely dispensable for normal development in mice but is associated with tumor growth in multiple cancer types, selective CDK2 inhibition represents an attractive therapeutic strategy.[1]
Emerging preclinical evidence suggests that CDK2 inhibition may be particularly effective in tumors that have developed resistance to CDK4/6 inhibitors, potentially providing a sequential treatment strategy for patients with progressive disease.[3]
Remove ads
Clinical development
As of August 2025, tegtociclib is in Phase 1b/2 clinical development, with studies evaluating both monotherapy and combination approaches.[1] The clinical program is designed to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of the drug in patients with advanced solid tumors, with a particular focus on hormone receptor-positive breast cancer.[6][7][8][9][10]
The combination studies are exploring tegtociclib in conjunction with endocrine therapy and potentially with other targeted agents, based on preclinical data suggesting synergistic effects when CDK2 inhibition is combined with hormonal blockade.[11][7][8][9][10]
Target population
Tegtociclib is being developed primarily for patients with hormone receptor-positive breast cancer, particularly those who have developed resistance to CDK4/6 inhibitor therapy.[1] This represents a significant unmet medical need, as patients who progress on CDK4/6 inhibitors currently have limited therapeutic options.[2]
The target population includes patients with advanced or metastatic HR-positive breast cancer who have received prior treatment with CDK4/6 inhibitors in combination with endocrine therapy.[12] Additionally, the drug may have applications in treatment-naïve patients with high cyclin E expression or other biomarkers predictive of CDK2 dependency.[11]
Remove ads
Biomarker considerations
The development of tegtociclib includes investigation of potential predictive biomarkers to identify patients most likely to benefit from CDK2 inhibition.[4] Key biomarkers under investigation include cyclin E expression levels, Rb protein status, and genomic alterations affecting the CDK2 pathway.[2]
High cyclin E expression has been associated with resistance to CDK4/6 inhibitors and may serve as a predictive biomarker for CDK2 inhibitor sensitivity.[3] Additionally, loss of Rb function, which occurs in a subset of breast cancers, may identify tumors that are particularly dependent on CDK2 for proliferation.[5]
Remove ads
Regulatory status
As of August 2025, tegtociclib has investigational status and has not been approved by any regulatory agency for clinical use. The drug is being evaluated in ongoing Phase 1b/2 clinical trials, with data expected to inform future registration-enabling studies.
See also
References
External links
Wikiwand - on
Seamless Wikipedia browsing. On steroids.
Remove ads