Recent advances in development of CDK7 inhibitors and their clinical trials: a narrative review.

Introduction

Cancer remains a leading global cause of mortality, with nearly 20 million new cases and 9.7 million deaths reported by World Health Organization in 2022. The most prevalent malignancies were lung (12.4%), breast (11.5%), colorectal (9.6%), prostate (7.3%) and gastric cancers (4.8%) ( 1 ). While recent therapeutic advances have improved cancer outcomes, significant challenges persist for patients with advanced disease due to treatment resistance, adverse effects, and limited efficacy. CDK7 inhibitors represent a promising therapeutic class under clinical investigation for multiple malignancies including hepatocellular carcinoma (HCC), leukemia, breast cancer, non-Hodgkin lymphoma (NHL), small cell lung cancer (SCLC), and triple-negative breast cancer (TNBC) ( 2 ).

CDK7, a key isoform of the cyclin-dependent kinases (CDKs) family, has demonstrated promising antitumor efficacy in recent clinical studies ( 3 - 7 ). However, no selective CDK7 inhibitors have been approved to date, with only five candidates reaching clinical trials ( 2 ). Two of these (LY-3405105, SY-1365) were discontinued due to insufficient activity and significant toxicity ( 8 , 9 ). Samuraciclib currently represents the most clinically advanced selective CDK7 inhibitor in phase II development ( 2 ). Further research remains warranted to develop safer, more efficacious CDK7-targeted therapies for solid and hematologic malignancies.

Current status of research on CDK7 and CDK7 inhibitors

Biological activity of CDK7

CDKs constitute a family of serine/threonine protein kinases that exist as inactive monomers and require binding to specific cyclins to form catalytically active heterodimers ( 5 ). These complexes regulate cell cycle progression by phosphorylating key substrates, thereby sequentially driving DNA synthesis and mitotic division to promote cellular proliferation ( 3 , 4 , 10 ). The human genome encodes 21 CDKs and over 15 cyclins, functionally categorized into two primary groups: cell cycle regulators (CDK1–6,14–18) and transcriptional regulators (CDK7–13,19–20) ( 10 ). CDK7 uniquely orchestrates both transcription initiation and cell cycle control through its ternary complex formation with cyclin H and the assembly factor MAT1 ( 11 ).

CDK7 forms catalytically active complexes through sequential assembly with cyclin H (binary complex) and MAT1 (trimeric CDK7-CyclinH-MAT1 complex), functioning as CDK-activated kinase (CAK) when phosphorylated. CAK regulates cell cycle progression via targeted phosphorylation: ( Figure 1 ) ( 3 , 6 ): (I) activating CDK4/6 to phosphorylate retinoblastoma (Rb) protein into its inactive state, driving G1-phase progression ( 12 , 13 ); (II) activating CDK2 to initiate S-phase transition (G1/S) ( 14 , 15 ); and (III) activating CDK1 to promote mitotic entry (G2/M) ( 14 , 15 ). CDK7 inhibition predominantly arrests cells in the G1 phase by blocking G1/S transition, with secondary G2-phase arrest impeding G2/M transition ( 3 , 6 , 12 - 16 ).

Besides, CDK7 additionally serves as a core subunit of the general transcription factor TFIIH (transcription factor II H) ( Figure 1 ) ( 17 , 18 ), which comprises ten subunits: seven structural components (p62, p52, p44, p34, p8, XPB, and XPD) and three catalytic elements (CDK7-cyclin H-MAT1). TFIIH regulates transcription through XPD-mediated tethering of the CDK7 complex ( 4 , 6 , 17 , 18 ). During RNA polymerase II-mediated transcription: (I) In initiation, TFIIH helicases unwind promoter DNA while CDK7 phosphorylates Ser5/7 residues of the RNA polymerase II c-terminal domain (CTD), facilitating promoter clearance ( 18 - 20 ). (II) CDK7 further phosphorylates the T-loop of CDK9, activating it to phosphorylate CTD Ser2, thereby promoting transcription elongation ( 6 , 21 - 23 ).

Finally, transcriptional regulation involving CDK7 has also been closely related to the occurrence of malignant tumors. CDK7 has been closely linked to a variety of oncological diseases ( 3 , 6 , 24 ). For example: (I) CDK7 inhibitor THZ1 can inhibit the transcription process of the super-enhancer-linked oncogene MYCN, thereby inhibiting the growth of related tumors [neuroblastoma (NB) ( 25 ), T-cell acute lymphoblastic leukemia (T-ALL) ( 26 ), SCLC ( 27 ), Peripheral T-cell lymphomas (PTCL) ( 28 ) and ovarian cancer (OC) ( 29 )]. (II) CDK7 complex CAK (CDK7-cyclin H-MAT1) is highly expressed in breast cancer, especially in estrogen receptor-positive (ER + ) and endocrine-resistant breast cancer, so CDK7 inhibitor CT-7001 is expected to be used in combination with endocrine therapy for the treatment of ER + breast cancer ( 30 ). (III) CDK7 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and its expression level in tumor tissues is negatively correlated with the prognosis. In 2019, Lu first revealed that the CDK7 dependent transcriptional addiction existed in a subgroup of PDAC cells, which provided a promising therapeutic strategy in CDK7-addictive PDAC ( 31 ). This research finding was further complemented in 2023 by the discovery by Kartha that only basal PDAC is sensitive to CDK7 inhibitor THZ1 compared to classical PDAC, making CDK7 inhibitors promising for the treatment of this disease ( 32 ). (IV) The Nathanael Gray team at the Dana-Farber Cancer Institute found that CDK7 has important implications in the pathogenesis of TNBC. It was shown that blocking the activity of the key regulator CDK7 rapidly inhibits the growth of TNBC cells, but not other subtypes of breast cancer cells ( 24 ). Interestingly, McDermott team reported that CDK7 inhibition was effective in all the subtypes of breast cancer in combination with epidermal growth factor receptor (EGFR) inhibitors ( 33 ). These results suggest that CDK7 inhibitors have a potentially broad use in breast cancer therapy, whether used as a single agent (SA) or alternatively, synergized with other anti-tumor drugs.

In summary, CDK7 serves as a critical regulatory node governing both cell cycle progression and transcriptional control, with frequent dysregulation observed across multiple malignancies. Its functional centrality in tumor cell proliferation and apoptosis underscores therapeutic potential. Selective inhibition of CDK7 activity disrupts oncogenic signaling pathways, demonstrating significant antitumor efficacy. Consequently, CDK7 represents a high-value pharmacological warranting development of potent, selective inhibitors for precision oncology applications.

Advances in CDK7 inhibitors

CDK7 has classical protein kinase folding like other members of the family, including N-terminal (13–96 residues) and C-terminal (97–311 residues), the ATP binding site is located between the N-terminal and C-terminus, which is highly conserved and has a large degree of homologous similarity ( 5 ), so that the first-generation ATP-competitive CDK7 inhibitors are basically non-selective for different CDK isoforms, which ultimately leads to more toxic side effects and a narrower therapeutic window of the drug in the clinical trials ( 7 ). Compared with the first-generation pan-CDK7 inhibitors, the second-generation selective CDK7 inhibitors have more potent activity, better selectivity and druggability. Selective CDK7 inhibitors currently under investigation are mainly divided into two categories: (I) selective covalent CDK7 inhibitors, such as phenylpyrimidines: THZ1 ( 34 ), YKL-5-124 ( 35 ), SY-1365 ( 36 ), etc . ; (II) selective non-covalent CDK7 inhibitors, such as purine isoform analogs: BS-181 ( 37 ), CT-7001 ( 16 ) and SY-5609 ( 38 ), etc. ( Figure 2 ); (III) and other CDK7 inhibitors in clinical studies ( Figure 3 ). We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-81/rc ).

Methods

First, we obtained the list of selective CDK7 inhibitors from the database CDDI (Cortellis Drug Discovery Intelligence) using the keyword “CDK7 inhibitor”. Second, we searched and studied relevant literature in the databases PubMed, ClinicalTrials.gov, and Google Scholar, using the keywords obtained from the CDDI-exported list.

We read the English research & clinical literature, and Table 1 summarizes the search methodology.

Update on progress of CDK7 inhibitors in clinical studies

CDK7 complexes with cyclin H and MAT1 to form the CAK, which drives cell cycle progression via T-loop phosphorylation of CDKs. Additionally, CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at Ser5/7 residues enables transcriptional initiation. Dysregulation of these processes represents a hallmark of tumorigenesis, with CDK7 overexpression correlating with oncogenesis across multiple malignancies, establishing it as a promising therapeutic target. While current clinical development of selective CDK7 inhibitors focused primarily on solid and gynecologic tumors, early-phase trials are exploring applications in non-oncological conditions. Ongoing development of novel selective CDK7 inhibitors may expand therapeutic utility across both oncologic and non-oncologic diseases. Recent clinical advances in CDK7 inhibitors are summarized in Table 2 .

Update on clinical studies of Samuraciclib hydrochloride (CT-7001, ICEC-0942)

Samuraciclib hydrochloride ((3R,4R)-4-[(7-benzylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino]methylpiperidin-3-ol hydrochloride) ( 2 ), designated CT-7001, is a selective CDK7 inhibitor with minimal activity against CDK1/2/4–6/9 and multiple non-CDK kinases ( Table 2 ). In 2021, samuraciclib received U.S. Fast Track designation for two indications: treatment of CDK4/6 inhibitor (CDK4/6i)-resistant hormone-receptor-positive (HR + ), human epidermal growth factor-2-negative (HER2 − ) advanced breast cancer in combination with fulvestrant; and treatment of locally advanced or metastatic TNBC with chemotherapy.

In 2017, a phase I/II trial ( NCT03363893 ) ( 39 ) was carried out to assess the tolerability, pharmacokinetics, and efficacy of samuraciclib. This multicenter study investigated samuraciclib monotherapy in patients with advanced solid malignancies [phase I; tumor types included TNBC, OC, SCLC, and prostate cancer (PC)]. The trial completed enrollment of 124 participants. The phase II component evaluated samuraciclib in combination with fulvestrant in participants with HR + and HER2 − breast cancer. So far, there have been several articles reporting on the progress of this clinical trial ( 30 , 41 - 43 ). In 2021, dose-escalation results from TNBC expansion cohort (M1B, 23 patients) established a preliminary recommended phase 2 dose (RP2D) of 360 mg once daily (OD), associated with low-grade drug reactions (AE). Dose-limiting toxicity (DLT) occurred in three of six patients at 480 mg OD (G3 diarrhoea, oral mucositis, vomiting) and in one of seven patients at 180 mg twice daily (bid) (G4 thrombocytopenia) ( 41 - 43 ). The M2A study treated 31 patients with post-CDK4/6i HR + /HER2 – breast cancer with samuraciclib (240 mg OD, n=6; 360 mg OD, n=25) plus fulvestrant. This combination demonstrated excellent tolerability and an acceptable safety profile, characterized by low-grade AE ( 30 , 43 ). Among 25 efficacy-evaluable patients, disease control included stable disease (SD) in 13 patients and partial response (PR) in three, yielding a clinical benefit rate (CBR) was 36.0% (9/25) and a median progression-free survival (PFS) of 3.7 months ( 30 , 43 ).

Update on clinical studies of (R)-roscovitine (seliciclib) (CYC-202, NSC-701554)

Seliciclib ((R)-2-((6-(benzylamino)-9-isopropyl-9H-purin-2-yl)amino)butan-1-ol) ( 2 ), designated CYC-202 or NSC-701554, is a small-molecule CDK inhibitor that induces tumor cell apoptosis ( Table 2 ). This broad-spectrum purine analog inhibitor inhibits CDK1, CDK2, CDK5, CDK7 and CDK9 (IC 50 ~ 0.2–0.7 µM) but shows minimal activity against CDK4, CDK6 and CDK8 (IC 50 >100 µM) ( 52 ). Currently in phase II clinical development for pituitary cushing syndrome ( NCT03774446 ) ( 45 ), the compound also shows therapeutic potential for abnormal cell proliferation disorders including rheumatoid arthritis, advanced solid tumors, and BRCA-mutated cancers ( 50 ).

Seliciclib was also investigated in a phase II clinical study ( NCT00372073 ) ( 49 ) for the treatment of non-small cell lung cancer (NSCLC). The aim of this clinical trial was to evaluate the safety and efficacy of oral seliciclib. Recruitment for this trial was terminated, with an actual enrollment of 187 participants. The recommended administration schedule for seliciclib is 1,200 mg bid for three consecutive days, repeated every two weeks (q2w). This clinical trial is evaluating its primary endpoint, PFS, which will be measured until disease progression.

Update on clinical studies of Q-901

Q-901 is a selective CDK-7 inhibitor (undisclosed structure) ( 2 ) currently in phase I/II clinical development ( NCT05394103 ) ( 56 ) for advanced solid tumors via intravenous infusion ( Table 2 ).

In 2022, Q-901 was investigated in a phase I/II trial ( NCT05394103 ) ( 56 ). This multi-center study enrolls adult patients with advanced solid tumors refractory to standard therapies. The primary objectives are to evaluate the safety, pharmacodynamics, and pharmacokinetics of Q901, a novel drug candidate, administered via intravenous infusion. Currently recruiting, the trial plans to enroll 130 participants. Patients will be assigned to cohorts in a dose-escalation phase to determine the RP2D for both Q901 monotherapy and Q901 in combination with pembrolizumab. Q901 is administered by 30-minute IV infusion on a once-weekly schedule for 4 weeks, followed by an every-two-weeks schedule thereafter. The dose-escalation design initiates with low doses, escalating to assess tolerability and identify the maximum tolerated dose (MTD). Patients are closely monitored for adverse events ( 56 ).

Preclinical studies demonstrate that Q-901 induces DNA damage response (DDR) impairment, providing a mechanistic rationale for its combination with DNA repair-targeting agents, such as poly(ADP-ribose) polymerase (PARP) inhibitors to enhance tumor cell killing. In the A2780 and OVCAR3 BRCA wild-type ovarian cancer models, the combination of Q-901 with a PARP inhibitor demonstrated significant tumor growth inhibition (TGI: 104%) compared to PARP inhibitor monotherapy (TGI: 15%) ( 58 ), indicating synergistic antitumor activity and supporting further development of this combination strategy.

Update on clinical studies of SNS-032

SNS-032 is a selective inhibitor of CDK2, CDK7, and CDK9 with IC 50 of 38–48, 62, and 4 nM, respectively ( 77 ) ( Table 2 ). Compared to flavopiridol and roscovitine, it demonstrates superior RNA synthesis inhibition and pro-apoptotic activity. This compound is currently undergoing clinical evaluation for hematologic malignancies including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) ( 2 , 78 ).

In a phase I trial ( NCT00292864 ) ( 60 ), SNS-032 was administered either as a single oral dose or via weekly 1-hour infusion to patients with metastatic solid tumors or refractory lymphoma. Enrollment was discontinued during dose escalation due to strategic pipeline reprioritization, with 21 of 25 planned participants enrolled. The primary objectives were to determine the MTD, the maximum administered dose (MAD), DLT and RP2D of SNS-032. Secondary objectives included assessment of safety, tolerability, and oral bioavailability. In 2008, Heath et al. reported a mean terminal half-life of five to ten hours and mean oral bioavailability of 19% (range, 4–33%) ( 61 ). Treatment-related adverse events included fatigue (25%) and nausea (20%) as the most common all-grade toxicities, with no grade 4 neutropenia, leukopenia, or thrombocytopenia observed. Among 20 response-evaluable patients assessed per RECIST criteria, progressive disease (PD) occurred in 65% (n=13), while SD represented the best response in 15% (n=3) ( 61 ).

Another phase I trial NCT00446342 ( 59 ) evaluated SNS-032 administered as a loading dose followed by weekly 6-hour infusions for three weeks per 28-day cycle in patients with CLL and MM. This completed trial enrolled 21 participants (n=21) with primary objectives to evaluate safety, tolerability, pharmacokinetic/pharmacodynamic (PK/PD) profile, and determine the RP2D of SNS-032. Tong et al. identified tumor lysis syndrome (TLS) as the DLT in CLL patients, establishing 75 mg/m 2 as the MTD for this cohort. In contrast, SNS-032 demonstrated favorable safety in MM patients with no DLTs observed. Pharmacokinetic analysis revealed supra-proportional exposure increases in both CLL and MM patients ( 78 ), diverging from prior observations of dose-proportional pharmacokinetics in advanced solid tumors ( 61 ). Minimal antitumor activity was demonstrated in both CLL and MM cohorts.

Update on clinical studies of XL-102

XL-102 is a potent, selective, orally bioavailable covalent inhibitor of CDK7, a key regulator of transcriptional machinery and cell cycle progression ( Table 2 ). Currently in early clinical development ( NCT04726332 ) ( 62 ), this compound is being evaluated for solid tumors as both monotherapy and as combination therapy.

The phase I trial ( NCT04726332 ) ( 62 ) evaluates XL-102 as monotherapy for malignant neoplasms and in combination regimens for advanced solid tumors, assessing safety, tolerability, pharmacokinetics (PK), antitumor activity, and biomarker profiling. This active, not recruiting trial ( NCT04726332 ) plans to enroll 373 participants. XL-102 monotherapy expansion cohorts include: Cohort D: TNBC; Cohort E: epithelial ovarian cancer (EOC); Cohort F: hormone receptor-positive breast cancer (HR + BC); Cohort G: metastatic castration-resistant prostate cancer (mCRPC). Besides, for combination expansion cohort experiments, drug Fulvestrant is administered with XL-102 in subjects with HR + BC (Cohort H). Drug Abiraterone/Prednisone is administered with XL-102 in subjects with mCRPC (Cohort I). The primary endpoint for dose escalation was determination of the MTD/recommended dose of XL102, assessed over 18 months. For cohort expansion, the primary endpoint was objective response rate (ORR), evaluated over 12 months ( 62 ).

In the preclinical studies, Gaur et al. ( 79 ) demonstrated that XL-102 induces p53-mediated leukemic cell elimination via the CDK7/c-Myc/p53 axis and overcomes venetoclax resistance, indicating potential efficacy against BCL-2-resistant acute myeloid leukemia (AML).

Update on clinical studies of SY-5609

SY-5609 ((3S)-7-(dimethylphosphoryl)-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile) ( 2 ) is an oral non-covalent CDK7 inhibitor currently in early clinical development for advanced malignancies including breast, colorectal, lung and ovarian cancers, as well as solid tumors with retinoblastoma (Rb) pathway alterations ( Table 2 ). This compound received U.S. orphan drug designation for pancreatic cancer in 2022 ( 2 ).

SY-5609 is in a multi-center, open-label Phase I trial ( NCT04247126 ) ( 63 ) expected to evaluate the recommended dose, safety, PK/PD, clinical activity, and induction of peripheral blood PD marker POLR2A ( 65 , 66 ). This completed first-in-human (FIH) study enrolled 105 participants. Two administration regimens were evaluated. One is the continuous daily dosing (CDD) of SA regimen, and the other is an intermittent dosing regimen (7 days on/7 days off; 7/7 schedule). In addition to monotherapy, SY-5609 is being developed in combination with: (I) Fulvestrant for CDK4/6 inhibitor-refractory HR + /HER2 – breast cancer. (II) Gemcitabine ± nab-paclitaxel in an expansion cohort assessing safety, tolerability, and preliminary efficacy at the recommended combination dose. Sharma et al. demonstrated improved tolerability with intermittent dosing (7 days on/7 days off) over continuous administration ( 67 ). As of January 13, 2023, 87 patients have been enrolled without reaching MTD for the intermittent 7/7 schedule. Most SA treatment-related AEs were grade 1–2. The 10 mg SY-5609 + gemcitabine cohort is currently enrolling. SY-5609 combinations with gemcitabine ± nab-paclitaxel showed predominantly low-grade AEs and acceptable tolerability. Among response-evaluable SA patients (n=29), 3/29 (10 mg intermittent 7/7) achieved SD versus 5/26 (19%) at 4–7 mg ( 66 ).

Another phase I trial ( NCT04929223 ) ( 64 ) is actively recruiting approximately 422 patients with metastatic colorectal cancer (mCRC) to evaluate SY-5609 monotherapy and combination regimens. Participants will be stratified into biomarker-defined cohorts based on tumor molecular profiling.

Update on clinical studies of BTX-A51

BTX-A51 (trans-N1-[5-Chloro-4-[5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl]pyrimidin-2-yl]cyclohexane-1,4-diamine hydrogen chloride) ( 2 ), designated A-51 or WXL-5846 ( Table 2 ), is an oral, small-molecule inhibitor targeting CK1α, CDK7 and CDK9. This compound elevates p53 protein levels through CK1α inhibition while suppressing super-enhancer-driven transcription of Myc and Mcl1. It was undergoing early clinical development for hematological malignancies including relapsed/refractory AML, high-risk myelodysplastic syndrome (MDS) and B-cell NHL, and advanced solid tumors.

BTX-A51 is in a clinical trial [ NCT04243785 ( 69 )] to evaluate the safety, toxicity, PK, as well as preliminary efficacy of BTX-A51 capsules in participants with relapsed/refractory AML or high-risk MDS ( 70 , 71 ). The primary aim is to define the DLTs, AEs, MTD and RP2D of BTX-A51. The recruitment status of this trial is recruiting, and the estimated enrollment is 80 participants. First, monotherapy cohort escalation study is designed to determine the DLTs and MTD of orally administered BTX-A51 in up to 35 participants who are evaluable for toxicity. The regimen is a cyclic three-week on/one-week off schedule, with each cycle lasting 28 days. After the MTD or highest dose achieved in phase 1a, phase 1b will focus on additional experience with safety and efficacy. Also, once the MTD and RP2D is available, azacitidine combination dose escalation studies will determine the recommended combination dose of BTX-A51 via oral and azacitidine via IV or SC 75 mg/m 2 QD on days 1–7 of each 28-day cycle. In 2022, Ball reported that monotherapy doses of 1–42 mg were administered orally three days (d)/week (wk) for three wk (in a 28-d cycle), whereas the 21 mg dose was given for four wk per 28-d cycle. Responses were not observed in MDS patients, and the PD data are not full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered three d/wk for four wk of a 28-day cycle with an acceptable safety profile and promising antileukemic activity in patents with heavily pretreated relapsed/refractory AML ( 70 ).

Another phase I clinical trial NCT04872166 ( 68 ), is an active, multicenter, open-label, single-arm study evaluating BTX-A51 in advanced solid tumors and non-Hodgkin lymphoma (NHL). With planned enrollment of 116 participants, this two-phase design includes: Phase 1a determines the DLTs, MTD, and RP2D of BTX-A51 (primary endpoint). Phase 1b expands the cohort to evaluate safety and efficacy in patients with MYC genomic amplified/overexpressed tumors. BTX-A51 is administered orally using a 5-days-on/2-days-off weekly schedule in 28-day cycles. Dose escalation employs six predefined cohorts (1×, 2×, 3.5×, 5×, 7×, 10× starting dose) to establish RP2D ( 68 ).

Update on clinical studies of LY-3405105 and SY-1365

The selective CDK7 inhibitor LY-3405105 was clinically evaluated for advanced solid tumors via oral administration ( Table 2 ). Development was discontinued in 2020 following termination of clinical trial ( NCT03770494 ) ( 72 ) due to insufficient efficacy ( 8 ).

SY-1365 (N-[(1S,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-1-methylcyclohexyl]-5-[[(2E)-4-(dimethylamino)but-2-enoyl]amino]pyridine-2-carboxamide) ( 2 ), designated mevociclib ( Table 2 ), was a selective CDK7 inhibitor evaluated intravenously in advanced solid tumors including OC and breast cancer. As the first selective CDK7 inhibitor to enter clinical investigation ( NCT03134638 ) ( 73 ), its development was discontinued in 2019. Preclinical/clinical data ( 36 ) indicated that sustained therapeutic CDK7 inhibition required higher doses or increased administration frequency, resulting in unacceptable treatment burden ( 9 ).

Perspectives

Advancing CDK7 inhibitor development requires multi-faceted innovation. Artificial intelligence (AI) and machine learning can revolutionize drug design by analyzing kinase inhibitor datasets to predict protein-ligand interactions and optimize structures, thus accelerating discovery of selective and potent agents.

Exploring CDK7 functions beyond cell cycle regulation and transcription, particularly in DDR, autophagy, and tumor microenvironment modulation, may reveal novel therapeutic targets. For instance, CDK7 inhibition could enhance the efficacy of DNA-damaging chemotherapy or disrupt cancer cell survival within the tumor niche.

Finally, integrating genomics, proteomics, and metabolomics enables comprehensive profiling of CDK7 inhibition, facilitating identification of biomarkers for treatment response, resistance, and toxicity. This supports patient stratification and personalized combination therapy.

Conclusions

Current clinical trials of CDK7 inhibitors reveal significant differences in efficacy between pan- and selective agents. Among phase II candidates, including samuraciclib, milciclib, seliciclib, and Q-901, only samuraciclib and Q-901 exhibit high selectivity for CDK7. Pan-CDK7 inhibitors such as seliciclib (targeting CDK1/2/5/7/9) and SNS-032 (targeting CDK2/7/9 and CCNE1) have shown limited clinical benefits: seliciclib failed to demonstrate significant advantages over placebo in treating adult cystic fibrosis regarding inflammation, pain, and quality of life, while SNS-032 showed poor tolerability and disease control in metastatic solid tumors or refractory lymphoma patients, with 65% experiencing PD and only 15% (three out of 20) achieving SD. In contrast, the selective CDK inhibitor samuraciclib has demonstrated promising efficacy in treating post-CDK4/6i HR + /HER2 – breast cancer, with 13 cases of SD, three PR, and an overall CBR of 36.0% (nine out of 25), suggesting that selective CDK7 inhibitors may offer superior safety and efficacy profiles.

CDK7 inhibitors are predominantly developed for treating advanced solid tumors, breast cancer, ovarian cancer, and lung cancer. Although selective inhibitors like XL-102 and SY-5609 are currently in phase I trials, samuraciclib received U.S. FDA Fast Track designation in 2021 for treating CDK4/6i resistant HR + /HER2 – advanced breast cancer, highlighting its potential. Despite challenges in developing pan-CDK7 inhibitors, CDK7 remains a promising target for cancer therapy, necessitating continued research efforts to enhance inhibitor selectivity and optimize therapeutic outcomes.

Supplementary

The article’s supplementary files as

Acknowledgments

None.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-81/rc

Funding: The work was supported by Start-up Fund for New Ph.D. Researchers of Suzhou Chien-Shiung Institute of Technology ; 2023 Provincial Universities Basic Science (Natural Science) Research Project ( No. 23KJB350008 ); Taicang Basic Research Program ( Nos. TC2021JC17 , TC2022JC32 and TC2021JC13 ); and Middle-Aged and Young Academic Leaders under the ‘Qinglan Project’ in Jiangsu Colleges and Universities [Letter of Jiangsu Provincial Department of Education , No. (2025) No. 16 ].

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-81/coif ). Z.G. is employed by Innovent Biologics (Suzhou) Co., Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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