We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage in vitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late-stage prostate cancer, a currently lethal disease.

P1/2, N=51, Recruiting, Zhejiang Genfleet Therapeutics Co., Ltd.

Enrichment of DNMT1 in FBXO32 promoter region led to increased DNA methylation and reduced transcription. Mechanistically, FBXO32 degraded CDK9 through promoting its ubiquitination.

Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials...Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

We explore these compounds for targeted protein degradation, offering a novel and potentially effective approach to cancer therapy. This cohesive strategy utilizes the combination of computational predictions and experimental insights, with the goal of advancing the development of effective anticancer therapeutics, targeting CDK9.

P1/2, N=130, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Mar 2024 --> Mar 2025

Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%)...Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.

P1, N=74, Terminated, Sumitomo Pharma America, Inc. | Trial completion date: Oct 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jan 2024; Sponsor's decision to terminate further development of the program.

P2, N=52, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

Flavopiridol potentiates the anti-tumor activity of gemcitabine by inducing cell cycle arrest and apoptosis. Its synergistic inhibition of PDAC cell proliferation, when combined with gemcitabine, positions flavopiridol as a promising candidate for cancer treatment.

Mutated non-phosphorylatable CDC23(S588A) affected the repair pathway choice by impairing HR and favouring error-prone NHEJ. This CDK9 role should be considered when designing CDK-inhibitor-based cancer therapies.

P1/2, N=95, Recruiting, Zhejiang Genfleet Therapeutics Co., Ltd. | Not yet recruiting --> Recruiting

Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

Compound 7e exhibited the most potent cytotoxic activity against A549 cell line (IC50: 0.155 µM) while compound 8d showed the most potent one against MCF7 cell line (IC50: 0.170 µM) in comparison with doxorubicin...Our findings by docking and experimental studies that compound 7e is a potent CDK2 inhibitor with IC50 of 0.149 µM, compared to the Roscovitine control drug with IC50 of 0.380 µM. We also found that compound 8d is a significant DHFR inhibitor with an IC50 of 0.199 µM, compared to Methotrexate control drug with IC50 of 0.131 µM. Evaluation of the antioxidant properties of ten compounds was also studied in comparison with Vitamin C. Compounds 1, 3, 6, 7c and 8e have higher antioxidant activity than Vitamin C which mean that these compounds can used as potent antioxidant drugs.

P1/2, N=210, Suspended, Cyclacel Pharmaceuticals, Inc. | Recruiting --> Suspended

P1/2, N=280, Recruiting, Kronos Bio | N=170 --> 280

Moreover, Atuveciclib interfered with the abnormal STAT3 signaling pathway through the inhibition of CDK9, which ultimately ameliorated psoriatic-like skin inflammation. These suggested that CDK9 inhibition is a potential strategy for batting psoriasis.

This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton's tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma...Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.

CDK5 might play important roles in bladder cancer progression and be a potential diagnostic and therapeutic target in the near future.

P1, N=60, Completed, Cyclacel Pharmaceuticals, Inc. | Active, not recruiting --> Completed

P1/2, N=330, Recruiting, Cyclacel Pharmaceuticals, Inc. | Trial completion date: Dec 2023 --> Jun 2025 | Trial primary completion date: Oct 2023 --> Apr 2025

P1, N=8, Active, not recruiting, Cyclacel Pharmaceuticals, Inc. | Trial completion date: Oct 2023 --> Jan 2024 | Trial primary completion date: Aug 2023 --> Mar 2023

P1, N=14, Completed, Cyclacel Pharmaceuticals, Inc. | Active, not recruiting --> Completed | N=25 --> 14 | Trial completion date: Sep 2023 --> Apr 2023

P1, N=5, Completed, Cyclacel Pharmaceuticals, Inc. | Active, not recruiting --> Completed | N=25 --> 5

In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1 mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.

Based on our work, we are proposing three potential therapeutic approaches to treat advanced ovarian cancer patients who exhibit low Caspase-8 expression and resistance to Carboplatin and/or Paclitaxel-combinations of (1) Carboplatin with small-molecule BRD4 inhibitors; (2) Paclitaxel with small-molecule BRD4 inhibitors, and (3) small-molecule BRD4 and CDK9 inhibitors. In addition, we are also proposing two predictive markers of chemoresistance-BRD4 and pCDK9.

MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use.

TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

Through rapid 'on-off' CDK9 inhibition, GFH009 exerts a proapoptotic effect on HHM preclinical models triggered by dynamic deprivation of crucial cell survival signals. Our results mechanistically establish CDK9 as a targetable vulnerability in assorted HHMs and, along with the previously shown superior class kinome selectivity of GFH009 vs other CDK9 inhibitors, strongly support the rationale for currently ongoing clinical studies with this agent in acute myeloid leukemia and other HHMs.

Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC values of 0.83, 2.12, 3.12, and 8.61 μM, respectively, which were comparable to that of Palbociclib and AZD5438. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

P1, N=30, Completed, Prelude Therapeutics | Active, not recruiting --> Completed

P1/2, N=40, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2023 --> Dec 2024

P2, N=52, Active, not recruiting, AstraZeneca | N=81 --> 52 | Trial completion date: Aug 2024 --> Dec 2024

CDK2/9 antagonism with CYC065 (Fadraciclib)-treatment disordered centrosome stoichiometry in aneuploid cancer cells, preventing centrosome clustering...Thus, CDK2 inhibition preferentially disorders centrosome stoichiometry in cancer cells. Engaging this disruption is a strategy to explore against aneuploid cancers in future clinical trials.

Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E and for CD30-postive pTCLs, brentuximab vedotin is approved...Using the MCL-1 inhibitor AZD5991, we have shown statistically significant benefit in survival when combined with CHOP in 2 MCL-1 dependent preclinical pTCL PDX models (Koch et al...These data suggested that treatment with AD4573 either as a monotherapy or in combination with CHOP, would be an effective therapeutic strategy in pTCL. AZD4573 monotherapy is currently being evaluated in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK in patients with relapsed/refractory pTCL.

The study is open to enrollment and registered at ClinicalTrials. gov (NCT05665530).

In a similar fashion, Venetoclax-driven BCL2 inhibition also potentiated the anti-tumor activity of PRT2527...Additionally, we demonstrated that PRT2527 potently inhibits growth in Ibrutinib-resistant MCL cell lines. Further work characterizing PRT2527 as monotherapy and in combination with BTKi and BCL2i in in vivo models of BTKi-resistant MCL and CLL is currently ongoing. Altogether these data provide a rationale for evaluating PRT2527 in combination with BTK and BCL2 inhibitors for the treatment of patients with relapsed/refractory hematologic malignancies.

We performed cell viability experiments on leukemia cell lines (MV4; 11, MOLM13, RS4; 11, THP1, SEM, KOPN8, NOMO1, HL60, ML2) with single, two and three drug combinations using a menin inhibitor (VTP50469), a DOT1L inhibitor (EPZ5676), and a CDK9 inhibitor (AZD4573). Based on our preclinical in vitro findings, the co-inhibition of menin-DOT1L or menin-CDK9 is a promising approach for the treatment of MLL-r leukemia. The varying responses of different MLL-r leukemia cell lines to drug combination treatment indicate that not all cases of MLL-r leukemia will respond uniformly to treatment combinations. Taken together, our data provide a strategy to determine optimal treatment combinations for personalized treatment of MLL-r leukemia.

It can also optimize the administration of various first-line drugs, including AKT inhibitors VIII Imatinib, Crizotinib, Saracatinib, Erlotinib, Dasatinib, Rapamycin, Roscovitine and Shikonin in BC patients. Finally, we employed machine learning techniques to construct a multi-omics prediction model(Risklight),with an area under the feature curve (AUC) of up to 0.89. With the help of CAG_score and Risklight, we reveal the signature of cholesterol homeostasis-related genes for angiogenesis, immune responses, and the therapeutic response in breast cancer, which contributes to precision medicine and improved prognosis of BC.

Furthermore, Z11 demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall, Z11 served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.

Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.