What CDK8 inhibitors are in clinical trials currently?

Introduction to CDK8
Cyclin-dependent kinase 8 (CDK8) is one of the key regulatory kinases associated with the Mediator complex and plays a pivotal role in transcription regulation, signal transduction and ultimately in controlling cell cycle progression. CDK8 has emerged over the past decade as an attractive drug target in oncology following the discovery that its dysregulation can drive oncogenic processes in various tumor types. Its modulation affects the transcriptional outputs of several oncogenes and tumor suppressors, thereby determining cell fate. The growing recognition of CDK8’s involvement in the modulation of complex gene expression programmes and its ability to influence key signaling pathways has accelerated efforts to develop small‐molecule inhibitors targeting this enzyme.

Role of CDK8 in Cellular Processes
CDK8 is involved in several cellular functions including the regulation of RNA polymerase II transcription, phosphorylation of transcription factors, and modulation of super-enhancer associated gene expressions. By interacting reversibly with the Mediator kinase module, CDK8 not only activates oncogenic transcription factors – such as via the Wnt/β-catenin and estrogen-inducible gene programs – but under certain contexts it can also contribute to tumor suppression. Its context-dependent function makes CDK8 a unique enzyme in that its inhibition may yield diverse outcomes depending on the cellular environment and the tumor type.

CDK8 as a Therapeutic Target
Based on a solid body of preclinical evidence, the pharmacological inhibition of CDK8 holds the promise to selectively modulate cancer cell transcription and impair tumor growth. CDK8 inhibition can have a dual effect: directly impacting tumor cell proliferation by downregulating oncogenic signaling and indirectly sensitizing cancer cells to conventional therapies. The promising preclinical data have fostered a number of clinical programs investigating CDK8 inhibitors as treatment options in advanced malignancies. The focus on achieving high selectivity has been paramount in order to minimize off-target effects that are common with early, more promiscuous CDK inhibitors.

Overview of CDK8 Inhibitors
There have been extensive efforts to develop inhibitors that target CDK8 with the aim of interrupting aberrant transcriptional processes in cancer cells. The design of these compounds has evolved over the years from initial nonselective ATP-competitive inhibitors to more refined molecules that target specific binding pockets and protein–protein interaction sites to achieve selectivity and favorable pharmacokinetic profiles.

Mechanism of Action
CDK8 inhibitors primarily function by binding competitively with ATP in the active site of the kinase domain, thereby disrupting the enzymatic activity of CDK8. This inhibition halts the phosphorylation of transcription factors and other Mediator subunits involved in driving oncogenic transcription. In some cases, the binding can induce conformational changes which affect the stability and assembly of the Mediator complex. Interestingly, since CDK8 has dual roles—both in promoting and in some instances restraining oncogenesis—its inhibition can reprogram cellular transcription profiles to favor anti-tumor outcomes. Structural biology and rational drug design approaches have been instrumental in identifying distinctive features of CDK8’s binding domain that can be exploited to develop selective inhibitors.

Development History
The development history of CDK8 inhibitors spans basic discovery work in kinase biology to advanced structure-guided drug design initiatives. Early efforts were largely hindered by the poor selectivity of first-generation CDK inhibitors, leading to broad toxicity and off-target effects. Subsequently, structural elucidation of CDK8 and its interaction with the Mediator complex provided the impetus for the design of more selective inhibitors, incorporating specific ligand motifs and exploiting unique hinge-region contacts. Several compounds have been reported with promising biochemical and cellular profiles that provided proof-of-principle for further clinical investigation. Today, the most notable compounds have progressed from preclinical characterization to clinical evaluation in various phases of human trials.

Current Clinical Trials of CDK8 Inhibitors
Recent years have seen the translation of multiple CDK8 inhibitors into the clinical arena. Advanced malignancies, especially those with limited treatment options such as advanced solid tumors, hematological malignancies and hormone-driven cancers, are key indications for these agents. In this context, the clinical studies are designed to primarily inform on safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and preliminary efficacy. The clinical candidates currently under investigation include TSN084 tablets, RVU120 (also known as SEL120) and BCD-115.

List of CDK8 Inhibitors in Trials
The foremost CDK8 inhibitors that have progressed into clinical trials include:

• TSN084 Tablets – TSN084 is under investigation in Phase I studies in patients with advanced malignant tumors. Two different clinical trial registrations document the same Phase Ia/Ib study with TSN084 tablets, registered under CTR20220834 and NCT06386705, where the objectives center on assessing safety, tolerability, and preliminary efficacy in this patient population.

• RVU120 (SEL120) – RVU120, sometimes referred to as SEL120, is another promising CDK8 inhibitor that has entered clinical trials. Multiple studies are evaluating RVU120 in a variety of settings including advanced solid tumors and hematological malignancies such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Clinical trials registered with numbers such as NCT05052255, NCT06268574, and NCT04021368 are exploring its pharmacokinetic and pharmacodynamic profiles, as well as its clinical efficacy both as a monotherapy and in combination regimens.

• BCD-115 – BCD-115 is being investigated in a multicenter open-label study targeting women with estrogen receptor-positive (ER(+)) HER2-negative locally advanced or metastatic breast cancer. This study combines BCD-115 with endocrine therapy and aims to evaluate safety alongside pharmacokinetic parameters, potentially taking advantage of CDK8 inhibition to modulate hormone-driven oncogenic transcription in breast cancer.

These candidates represent the forefront of clinical translational efforts in modulating CDK8 activity as a therapeutic strategy.

Phases and Objectives of Trials
The clinical programs for these inhibitors follow a classical phase I/II design typical of early oncology drug development:

• Phase I Studies (Dose Escalation/Expansion Studies):
  – For TSN084 tablets, the trials are structured as dose-escalation studies to evaluate the maximum tolerated dose (MTD), along with safety, tolerability, and a detailed characterization of the pharmacokinetic and pharmacodynamic profile. These studies, by design, enroll patients with advanced malignant tumors who have exhausted standard therapies. The primary endpoint is safety and determination of an optimal dose for further study, with secondary endpoints including preliminary signals of efficacy.

  – RVU120’s Phase Ia/Ib studies similarly focus on defining the safety and tolerability of the compound. These studies stratify patients according to tumor type (solid tumors versus hematological malignancies such as AML/MDS) and monitor dose-limiting toxicities (DLTs), biomarker modulation (e.g., phosphorylation of STAT1, which is a known substrate of CDK8), and response rates. Some trials also incorporate combination strategies with other agents such as Venetoclax to potentially enhance efficacy in resistant populations.

• Phase II Studies (Proof of Concept/Efficacy-Based Studies):
  – Although the current focus is on Phase I safety data, some of the RVU120 trials are already extending into early Phase II designs, looking at expansion cohorts in specific indications like AML or high-risk MDS to assess efficacy outcomes.
  – BCD-115 is similarly structured in a non-comparative two-stage Phase 1a/1b study where the combination of the CDK8 inhibitor with endocrine therapy is being evaluated particularly for its effect on progression markers in ER(+) breast cancer. The endpoints include tumor response rates, progression-free survival (PFS) in addition to standard safety assessments.

Throughout these studies, pharmacodynamic biomarkers such as alterations in oncogenic transcription, STAT phosphorylation levels, and changes in gene expression patterns related to the CDK8 pathway are being monitored to correlate with clinical outcome. Time points for sample collection, advanced PK/PD assessments and biomarker evaluation ensure that dosing schedules and target engagement are well characterized for these candidate drugs.

Preliminary Results and Efficacy
While full publications of the trial data are pending, the preliminary results reported in various study registries and updates suggest that:

• TSN084 Tablets – The early-phase trials have demonstrated an acceptable safety profile with manageable toxicities in heavily pre-treated patients. Some initial observations have indicated that TSN084 results in dose-dependent modulation of target biomarkers. Although objective responses are yet to be robustly reported, stable disease in certain patient cohorts has been noted, which is promising considering the advanced stage of disease in the study population.

• RVU120 (SEL120) – Preliminary clinical data from Phase I studies reveal that RVU120 is generally well tolerated with a safety profile consistent with its mechanism of selectively inhibiting CDK8. Pharmacodynamic assessments have revealed effective target engagement, for instance by reducing phosphorylation levels of CDK8 substrates. In AML and MDS patient cohorts, early signals of anti-leukemic activity have been observed, with some patients achieving partial responses or disease stabilization. Furthermore, combination studies with Venetoclax have demonstrated an encouraging synergistic effect, garnering further interest in measuring response rates in these high-risk populations.

• BCD-115 – For patients with ER(+) advanced breast cancer, the combination of BCD-115 with endocrine therapy is being closely monitored for potential efficacy benefits. Early data indicate that BCD-115 may augment the effect of endocrine therapies by downregulating specific gene expression cascades that are regulated by CDK8, translating into improved clinical outcomes such as reduced tumor burden. Safety outcomes in these early investigations have been promising, with adverse events being manageable within the clinical trial setting.

These preliminary outcomes support the continued clinical evaluation of these CDK8 inhibitors and underscore the importance of using biomarker-driven endpoints to optimize dosing strategies and assess therapeutic effectiveness in a heterogeneous population.

Challenges and Future Perspectives
The translation of CDK8 inhibitors from bench to bedside, while promising, still encounters several challenges that need to be addressed to maximize clinical benefit. Regulatory affairs, patient stratification and establishing robust efficacy endpoints remain the key hurdles that will define the future landscape of these agents.

Challenges in Development
One of the main challenges in the clinical development of CDK8 inhibitors is achieving a balance between effective target inhibition and maintaining an acceptable safety profile. Given that CDK8 plays a role in both oncogenic and normal physiological transcriptional regulation, achieving selectivity is paramount. Early compounds suffered from broad inhibition of multiple CDK family members, resulting in off-target toxicities. However, rational drug design focused on the unique structural features of CDK8 has helped address these issues in newer compounds such as TSN084, RVU120, and BCD-115.

Another challenge is the context-dependent role of CDK8 in cancer. In some tumor types, CDK8 acts predominantly as an oncogene, while in others it may have tumor-suppressive functions. This duality necessitates careful patient selection and biomarker identification to predict response. The incorporation of pharmacodynamic biomarkers (for example, reduced phosphorylation of STAT1) and genomic profiling in clinical trials is vital to address this challenge.

Additionally, the complexity of the tumor microenvironment and heterogeneity among patient populations make it challenging to interpret early signals of efficacy. Advanced malignancies are often resistant to therapeutic interventions, and multiple dosing schedules as well as combination strategies (e.g., with Venetoclax in AML or endocrine agents in breast cancer) are being explored to overcome these limitations.

Potential Future Applications
Despite the challenges, the promising early clinical results point to a variety of future applications for CDK8 inhibitors. Their ability to modulate transcription makes them potential candidates not only in oncology but possibly also in inflammatory diseases and conditions driven by dysregulated immune responses. The context-specific effects of CDK8 inhibition open avenues for personalized therapy in cancers with distinct molecular profiles. For example, in hormone-driven cancers (as suggested in the BCD-115 study) and in hematologic malignancies with reliance on aberrant transcriptional signals (as in the case of RVU120 trials), CDK8 inhibitors may provide an innovative therapeutic option.

Combination therapy represents another future application, where CDK8 inhibitors are integrated with other targeted therapies or chemotherapeutics to improve clinical outcomes. Preliminary combination regimens, such as pairing RVU120 with Venetoclax in AML patients, indicate a potential for synergy that warrants further investigation. This strategy may also extend to the enhancement of immunotherapy responses, as CDK8 inhibitors could potentially modulate tumor antigens and the immune microenvironment.

Regulatory and Market Considerations
From a regulatory perspective, the path to approval for CDK8 inhibitors will require comprehensive demonstration of both safety and clinical benefit in well-designed trials. Regulatory agencies will demand robust data from phase I/II trials, including detailed PK/PD characterization and biomarker validation. Given the novelty of the target and the complexity of its biological roles, early and continuous dialogue with regulatory bodies will be essential.

Market considerations also play an important role as CDK8 inhibitors will be competing in a crowded oncology landscape. While there is significant unmet need in advanced malignancies, especially in patients with resistant or refractory disease, the commercial success of these agents will depend on clear differentiation from existing therapies and demonstration of a favorable therapeutic index. Additional factors, such as the ability to identify responsive subpopulations through biomarkers, will be crucial to maximize market penetration and clinical uptake.

A coordinated effort among pharmaceutical companies, clinical researchers, and regulatory bodies will be vital in streamlining development pathways and ensuring that these novel agents reach patients efficiently. Negotiating the intellectual property landscape and patent protections, as seen with multiple patents in the CDK8 inhibitor space, will further help maintain competitive advantage and drive innovation.

Conclusion
The current clinical pipeline for CDK8 inhibitors reflects a robust effort to translate promising preclinical findings into meaningful therapies for advanced malignant diseases. The compounds currently in clinical trials – TSN084 tablets, RVU120 (SEL120), and BCD-115 – each represent a distinct strategic approach to targeting CDK8, offering diverse opportunities for therapeutic intervention. TSN084 is being evaluated in multiple Phase I studies in advanced malignant tumors with an emphasis on safety and pharmacologic modulation, while RVU120 is undergoing clinical testing in both solid and hematologic malignancies, including combination trials with agents like Venetoclax to enhance anti-leukemic efficacy. In parallel, BCD-115 is under clinical evaluation in ER(+) HER2(–) breast cancer in combination with endocrine therapy, highlighting the potential for CDK8 inhibitors in hormone-driven cancers.

From a general perspective, these clinical programs underscore the importance of understanding the multifaceted role of CDK8 in regulating both oncogenic and normal cellular processes. Specifically, the detailed PK/PD studies, biomarker-driven patient stratification and advanced dosing schedules pave the way for optimizing CDK8 inhibition as an anticancer strategy. More specific insights from these trials reveal that despite the challenges related to target selectivity and tumor heterogeneity, the preliminary data are encouraging with regards to safety and potential clinical benefit. Moreover, the exploration of combination therapy regimens to overcome potential drug resistance further broadens the therapeutic application of these inhibitors.

On the global scale, the progress in clinical development coupled with emerging regulatory guidelines and the extensive patent landscape has created a promising ecosystem for CDK8 inhibitors. The successful integration of these agents into clinical practice will likely depend on continued collaboration between academia, the pharmaceutical industry and regulatory agencies. In summary, while challenges remain — including defining the optimal therapeutic window, managing on-target effects and establishing clear biomarkers of response — the evolving clinical results strongly advocate for the continued investigation and eventual clinical incorporation of CDK8 inhibitors. These developments not only promise to address significant unmet needs in oncology but also offer the potential to redefine targeted therapy paradigms in diseases driven by aberrant transcriptional regulation.

In conclusion, the current clinical trials of CDK8 inhibitors illustrate a dynamic and evolving field with multiple candidates showing promise in early-stage human studies. TSN084 tablets, RVU120 (SEL120), and BCD-115 represent the forefront of this innovation, each undergoing rigorous evaluation to confirm their safety profiles, determine ideally efficacious doses and assess preliminary antitumor activity. As these trials progress, detailed biomarker assessments and combination therapy strategies are likely to enhance our understanding of how best to harness CDK8 inhibition to improve patient outcomes. The ongoing clinical efforts, supported by robust preclinical data and strategic trial designs, suggest that CDK8 inhibitors may soon become an integral part of the targeted therapy arsenal for various advanced cancers, thus marking a significant milestone in precision oncology.