P1/2, N=120, Active, not recruiting, Ryvu Therapeutics SA | Recruiting --> Active, not recruiting

P2, N=230, Recruiting, Ryvu Therapeutics SA | Not yet recruiting --> Recruiting

The findings highlighted the following: (i) the pronounced in vitro SI values of anti-HCMV activity obtained with CDK8 inhibitors; (ii) a confirmation of the anti-HCMV efficacy by CDK8-siRNA knock-down; (iii) a CDK8-dependent reduction in viral immediate early, early, and late protein levels; (iv) a main importance of CDK8 for viral late-stage replication; (v) several mechanistic aspects, which point to a strong impact on viral progeny production and release, but a lack of CDK8 relevance for viral entry or nuclear egress; (vi) a significant anti-HCMV drug synergy for combinations of inhibitors against host CDK8 and the viral kinase vCDK/pUL97 (maribavir); (vii) finally, a broad-spectrum antiviral activity, as seen for the comparison of selected α-, β-, γ-, and non-herpesviruses. Conclusions. In summary, these novel data provide evidence for the importance of CDK8 as a positive regulator of herpesviral replication efficiency, and moreover, suggest its exploitability as an antiviral target for novel strategies of host-directed drug development.

CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

Furthermore, in vivo, animal experiments confirmed that circ-CDK8 interference inhibited OSCC cell proliferation and SLC7A11 expression. Collectively, this study revealed a novel strategy to upregulate erastin-induced ferroptosis in OSCC cells via the circ-CDK8/miR-615-5p/SLC7A11 axis, providing new insights into OSCC and a potential therapeutic strategy for OSCC.

P2, N=230, Not yet recruiting, Ryvu Therapeutics SA

Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition, acceptable clearance, and high oral bioavailability in multiple preclinical species. Robust in vivo PD and efficacy studies in mice models further demonstrated its potential use as mono- and combination therapy for the treatment of cancers.

CDK8 overexpression and miR-193a-5p silencing attenuated the effects of si-HEIH-induced inhibition on the proliferation, migration, and invasion of HCC cells. Silencing HEIH restrained the proliferation, migration, and invasion of HCC cells via the miR-193a-5p/CDK8 axis.

A NOTCH-TBC1D15 inhibitor was found to inhibit NOTCH-dependent pathways and exhibited potent therapeutic effects in PDX mouse models. This unique targeting of the NOTCH-TBC1D15 interaction not only normalized the perinuclear localization of mitochondria but also promoted potent cytotoxic effects against TICs to eradicate patient-derived xenografts through NOTCH-dependent pathways.

P2, N=94, Recruiting, Ryvu Therapeutics SA

P2, N=41, Not yet recruiting, GCP-Service International West GmbH

P1, N=112, Active, not recruiting, Ryvu Therapeutics SA | Recruiting --> Active, not recruiting

Importantly, compound 12 showed relative good bioavailability (F = 38.80%) and low toxicity in vivo. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

P2, N=98, Recruiting, Ryvu Therapeutics SA | Trial completion date: Dec 2027 --> Sep 2026 | Trial primary completion date: Jun 2027 --> Feb 2026

P1/2, N=120, Recruiting, Ryvu Therapeutics SA | Trial completion date: Nov 2023 --> May 2025 | Trial primary completion date: Nov 2023 --> May 2025

P2, N=98, Recruiting, Ryvu Therapeutics SA | Not yet recruiting --> Recruiting

P2, N=98, Not yet recruiting, Ryvu Therapeutics SA

RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance.

Moreover, single-cell studies offer insights into its inhibitory effects on LSC-enriched populations and capacity for inducing differentiation. Overall, these results support RVU120 as a frontline candidate in AML therapy, countering therapeutic failure caused by persistent LSCs.

We investigated the expression of mediator complex components in a large database of MDS CD34+ marrow samples and age-matched controls. Our findings revealed that MED12, a critical component of the mediator complex, was significantly overexpressed in MDS samples from refractory anemia with excess blasts (RAEB), a higher risk subset of MDS(p=0.018) (Fig A). Furthermore, we observed that this overexpression of MED12 was associated with a higher rate of transformation to AML.

The presented results provide clinical and preclinical evidence for RVU120 as a candidate for a novel erythroid stimulating agent. Treatment with RVU120 could be a promising addition to the current treatment options for patients with lower-risk MDS who are transfusion-dependent and failing first-line therapies.

In the ongoing phase 1 trial, RVU120 shows clinical activity in both AML and HR-MDS, inducing RBC transfusion independence and blast reduction with a tolerable safety profile. Clearance of BM blasts including a formal CR were observed in patients treated at different dose levels. Relevant target inhibition is achieved from 110 mg onwards with expected higher pSTAT 5 inhibition with further dose escalation.

RECIST assessments of 15 patients demonstrated radiologic SD in 13 patients. Dose escalation is currently ongoing with PK modeling indicating high target engagement.

Furthermore, we observed that CDK8, EEF1A1, and NTN1 mediated the regulation of c-myc and cyclin D1 by miR-PC-2869 in MG63, SW1353, and antler cartilage cells. Overall, our work uncovered the cellular functions and underlying molecular mechanism of antler-derived miR-PC-2869, highlighting its potential as a therapeutic candidate for bone cancer.

Selective inhibitors of Bcr-Abl (prototype – imatinib mesylate, IM, Gleevec®) cause a therapeutic effect in the treatment of the primary process...Senexin B (SenB) and SNX631 were used for selective inhibition of CDK8/19, to suppress Bcr-Abl – IM, dasatinib, nilotinib, PF-114.Results and DiscussionsIt was found that CDK8/19 inhibition by SenB alone does not have an antiproliferative effect on CML cells...These changes were not demonstrated in KU812, where neither SenB sensitization, nor changes in expression of CKIs and c-Myc level were detected.ConclusionInhibition of CDK8/19 helps to overcome the delay of the cell cycle caused by the Bcr-Abl antagonist in CML cells and increase the death of tumor cells. The absence of general toxicity of CDK8/19 inhibitors during prolonged treatment under experimental conditions allows us to recommend CDK8/19 inhibition with targeted therapy of Bcr-Abl-positive tumors in prospect.

Western blotting results showed that PPM upregulation of miR-26b-5p suppresses NF-κB/p65 signaling pathway in HepG2 cells by targeting of CDK8. The present results suggested that miR-26b-5p may function as a target gene of PPM and may serve a role in hepatocellular carcinoma treatment.

Results from patients dosed up to 110 mg have shown a favorable safety profile of RVU120. Clinically significant signs of efficacy were observed above 100 mg indicating that higher exposure mayresult in more pronounced anti-leukemic activity of RVU120. Currently available data warrant further exploration of RVU120 in AML and HR-MDS and enrollment is ongoing at 135 mg.

The results in animal model also showed that E966-0530-45418 exhibited anti-metastatic properties in vivo. Our study demonstrated that E966-0530-45418 has great therapeutic potential in the treatment of metastatic prostate cancer.

Senexin B, a non-toxic selective inhibitor of cyclin-dependent protein kinases 8 and 19 (CDK8 and CDK19), in combination with γ-photon irradiation in doses of 2-10 Gy increased the death of colon adenocarcinoma cell line HCT116 (intact p53) in a logarithmically growing culture, which was accompanied by the prevention of cell cycle arrest and a decrease of "senescence" phenotype. The effect of senexin B in cells with intact p53 is similar to that of Tp53 gene knockout: irradiated HCT116p53KO cells passed through the interphase and died independently of senexin B. The inhibitor reduced the ability of cells to colony formation in response to irradiation; p53 status did not affect the effectiveness of the combination of radiation and senexin B. Thus, the CDK8/19 inhibitor senexin B increased cell sensitivity to radiotherapy by mechanisms dependent and independent of p53 status.

In addition, compound 43 showed relatively good bioavailability (F = 28.00%) and could inhibit the growth of AML tumors in a dose-dependent manner in vivo. This study facilitates the further development of more potent CDK8 inhibitors for the treatment of the AML.

It also showed an efficacy in a murine colon cancer B16F10 metastasis model. In addition, ABM-3249 displayed a good safety margin in a preliminary tox screen in rodents.

RVU120, a first in-class CDK8/19 inhibitor in phase I clinical trial demonstrated preclinical efficacy in acute myeloid leukemia PDX models. The potential benefit of CDK8/19i+niraparib combination will be further explored in PARPi-resistant models. Molecular studies are underway to explore potential biomarkers associated with synergy response, and to analyze the downstream effects on DNA Damage Response.

The role of NEAT1 overexpression in the biological phenotype of ovarian cancer cells was counteracted by shCDK19. In conclusion, EVO attenuates ovarian cancer cell progression via the NEAT1-miR-152-3p-CDK19 axis.

The newly identified miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop plays an important role in inflammation-related GC progression and may serve as a promising therapeutic target for GC.

TRIM31 loss led to a lower mouse survival rate under stress conditions of 5-fluorouracil (5-FU) administration, which was correlated with a lower number of HSPCs...Mechanistically, we found that ubiquitin-mediated degradation of CDK8 was impaired by TRIM31 deletion, which further induced transcriptional expression of PBX1 and Cyclin D1. Taken together, these findings reveal the function of TRIM31 in regulation of hematopoietic stem cell homeostasis and leukemia initiation; and indicate the physiological importance of TRIM31 in leukemia development at early stage of disease.

In vitro ADME, pharmacological kinetics, and toxicity of MK256 were profiled to evaluate the drug properties of MK256. Our results show that MK256 is a novel CDK8 inhibitor with a desirable efficacy and safety profile and has great potential to be a promising drug candidate for AML through regulating the STAT pathway.

Clear hallmarks of erythroid differentiation were further identified in several patients by specific changes in surface markers. These patients achieved meaningful clinical responses such as reduction of blasts and transfusion independence, respectively.

In the dose-escalation phase of the study, RVU120 shows clinical activity in AML and HR-MDS with a tolerable safety profile. Relevant target inhibition is achieved at the current dose level and is expected to increase at higher doses. Currently available data warrant further testing of RVU120 in hematologic disorders, and dose escalation in the Phase Ib study continues.