Consistent with this observation, 18F-FLT PET was able to differentiate the resistance to Palbociclib from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in OVCAR-3 model. This work highlights the utility of 18F-FLT PET as a quantitative, non-invasive biomarker which provides whole-body information. 18F-FLT PET has potential to be a biomarker in novel CDK inhibitor clinical trials to evaluate Palbociclib resistance and identifying responding and non-responding patients.

More significantly, 46 exhibited great safety properties and favorable pharmacokinetic profiles in vivo. All these results demonstrated that 46 was a potential candidate of novel anticancer drugs.

P1, N=90, Active, not recruiting, NiKang Therapeutics, Inc. | Recruiting --> Active, not recruiting

In this study, three series of compounds were designed and synthesized, using the CDK2 inhibitor fadraciclib (CYC065) as the lead compound, with 9H-purine as the core structure...This study evaluated the impact of substitutions at the 2, 6, and 9 positions of the purine ring on the activity of CDK2 small molecule inhibitors. The findings offer a theoretical foundation for future research, broadening the structural diversity and scope of CDK2 inhibitor studies.

P1/2, N=75, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

A comparison of essential genes for tumor cells survival identified CDK2 as a functional vulnerability in canine mammary tumors (CMTs) that can be targeted with the PF3600 inhibitor. Additional potential targets were also uncovered, providing insights for personalized cancer treatments in dogs.

Multiplexed immunofluorescence of 225 ovarian patient tumors reveals that at least 18% of tumors express high Cyclin E1 and high p16, a group that we expect to be particularly sensitive to CDK2 inhibition. Thus, p16 may be a useful biomarker for identifying the patients most likely to benefit from CDK2 inhibitors.

PGT and seliciclib (internal standard) chromatographic conditions optimisation, revealed favourable use of isocratic mobile phase consisting of methanol:ammonium acetate buffer (70:30v/v, pH5.0) pumped into C18-column (150mm length×4.6mm internal diameter, 5μm particle size), at 1mL/min flow rate. HPLC-FD method was successfully applied to study PGT pharmacokinetics in rats. In conclusion, this study introduces a reliable analytical method of PGT in plasma for routine use in therapeutic drug monitoring for quality assurance and clinical follow-up.

BLU-222 demonstrated robust activity in combination with carboplatin or paclitaxel in CCNE1-aberrant models, rendering chemotherapy-resistant tumors strongly sensitive to the combination. These findings demonstrate that response to CDK2 inhibition by BLU-222 can be further predicted using a combinatorial biomarker signature that could refine patient selection criteria in CCNE1-high patients and support clinical development.

CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315...These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.

P1/2, N=155, Terminated, Pfizer | Phase classification: P2 --> P1/2 | Active, not recruiting --> Terminated; Per business decision, but not due to safety concerns or regulatory request.

Taking the CDK2/9 inhibitor CYC065 as the positive control and an in-house library compound (64) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure-activity relationships (SAR)...After conducting selectivity testing against CDK2/9 kinase, compound B5 demonstrated approximately five-fold greater selectivity towards CDK9-cyclinT1 over CDK2-cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors.

We confirmed the potential importance of cell cycle-mediated regulation of C/EBPδ by showing that four of the most potent C/EBPδ activators-R547, PHA793387, AZD5438 and AT7519, all multi-cyclin-dependent kinase (CDK) inhibitors-limited the clonal expansion of PDAC cells. Next to providing a valuable selection of C/EBPδ-modulating compounds for the use in preclinical studies, this report contributes to our understanding of the molecular regulatory mechanisms of C/EBPδ in general and in PDAC in particular.

P1, N=90, Recruiting, NiKang Therapeutics, Inc. | Trial completion date: May 2025 --> Mar 2027 | Trial primary completion date: Mar 2025 --> Nov 2025

P1, N=40, Active, not recruiting, Regor Pharmaceuticals Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2024 --> Jul 2025

P1/2, N=366, Active, not recruiting, Blueprint Medicines Corporation | Recruiting --> Active, not recruiting

Low numbers limit conclusive clinical outcome reporting. High PD-1 expression on post-treatment TILs encourages the addition of an immune checkpoint inhibitor to TG02 and potentially other studies of peptide vaccines in future studies.

The molecular docking simulation toward CDK2 protein specified the best docking score of tetrazinethione 7 followed by sulfonamide derivative 4, compared to doxorubicin and roscovitine (kinase inhibitor). Their favorable oral bioavailability and drug-likeness characteristics were demonstrated by a modeling pharmacokinetics investigation. This research could help create novel antiproliferative drugs that are both efficient and selective.

P1/2, N=204, Recruiting, AstraZeneca | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Jun 2025 --> May 2026

P1, N=604, Recruiting, Incyte Corporation | N=340 --> 604 | Trial primary completion date: Apr 2024 --> Aug 2025

The research conducted yielded one compound ZINC11784547 has demonstrated robust binding affinity, favorable ADME features, less toxicity, remarkable stability, and cytotoxic effect. The identified compound holds promise for promoting cancer cell death through CDK12 inhibition.

Patient-derived ovarian cancer organoid models were established to evaluate the effectiveness of TQB3616...Overall, our findings suggest that TRIM4 modulates ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitors in ovarian cancer treatment. TRIM4 may serve as a valuable biomarker for predicting sensitivity to CDK4/6 inhibitors in ovarian cancer.

P2, N=33, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P1, N=138, Recruiting, BeiGene | Trial completion date: Dec 2026 --> Feb 2028 | Trial primary completion date: Dec 2026 --> Feb 2028

Among the synthesised compounds, 2-(pyridin-3-yl)-4-(pyridin-3-yl)-5,6-dihydrobenzo[h]quinazoline 8b and 4-(2-(pyridin-3-yl)-5,6 dihydrobenzo[h]quinazolin-4-yl) phenol 5g exhibited potent anticancer activity compared to (R)-Roscovitine...Furthermore, the efficacy of compound 5g was validated through an in vitro CDK2/cyclin A2 enzyme inhibition assay. Interestingly, the observed CDK2 inhibitory activity showed a good correlation with the corresponding value for the antiproliferative activity of the tested compounds.

P1, N=64, Recruiting, Regor Pharmaceuticals Inc. | N=18 --> 64

In silico molecular docking studies revealed that compounds 4, 7a, 7d, and 9 adopt a similar binding mode as AT7519 (I) within the CDK2 binding site...Based on these findings, it was concluded that the synthesized pyrazole derivatives, particularly compound 4, show potent CDK2 inhibition and significant anticancer activity, with promising drug-like properties and minimal toxicity. This positions them as strong candidates for further development as CDK2-targeting anticancer agents.

P1, N=40, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

The three promising anti-proliferative hybrids (1a, 8a, 13a) were selected for the assessment of their in vitro inhibitory kinase activity against CDK2/GSK3β using roscovitine (IC50 = 0.88 μg mL-1) and CHIR-99021 (IC50 = 0.07 μg mL-1) as references, respectively...Moreover, it resulted in an increase in Bax and caspase-3 with a decrease in Bcl-2 levels in HepG2 cells compared with untreated cells. Finally, in silico drug likeness/ADME prediction for the three potent compounds as well as a molecular docking simulation study were conducted in order to explore the binding affinity and interactions in the binding site of each enzyme, which inspired their usage as anti-proliferative leads for further modification.

N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.

Additionally, 5g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM)...Moreover, it triggered cell death by apoptosis and cell cycle arrest in G2/M. Taken together, 5g merits further investigation in PKPD research to discover a potential therapeutic candidate against cancer.

Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.

P3, N=287, Active, not recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2025

P1/2, N=192, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | Trial completion date: Dec 2026 --> Aug 2026 | Trial primary completion date: Dec 2026 --> Aug 2026

P1, N=8, Completed, Cyclacel Pharmaceuticals, Inc. | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> May 2024 | Trial primary completion date: Mar 2023 --> Feb 2024

Besides, molecular docking simulation of the synthesized oxindole-benzothiazole hybrid 9o proved the expected binding mode which involves the accommodation of the oxindole moiety in the ATP binding pocket where it is involved in hydrogen bonding and hydrophobic interactions with the essential amino acids in the hinge region while the benzothiazole moiety is oriented toward the solvent region. Investigation of the physicochemical properties of the hybrids 9a-r highlights their acceptable ADME properties that can be somewhat developed for the discovery of new anticancer agents.

Additionally, the dual-luciferase reporter assay and Pearson correlation coefficient analysis proved that circRACGAP1 acted in NSCLC cells by negatively regulating miR-1296 expression and positively regulating CDK2 expression. In summary, our study revealed that circRACGAP1 promoted NSCLC cell proliferation by regulating the miR-1296/CDK2 pathway, providing potential diagnostic and therapeutic targets for NSCLC.

A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.

Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in PCa. Further, high MYBL2 activity identifies PCa that would be responsive to CDK2 inhibition.

P1, N=18, Recruiting, Regor Pharmaceuticals Inc. | Trial completion date: Aug 2024 --> Sep 2026 | Trial primary completion date: Feb 2024 --> Dec 2025

In silico docking of the benzimidazole-oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK-3β revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a-x exhibit satisfactory drug-likeness properties for drug development.