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

The ligand 68Ga-10c demonstrated high absorption in tumor 5 min after injection and sustains long-term imaging within 3 h. Furthermore, 68Ga-10c exhibited slow clearance within the tumor and was predominantly metabolized in both the liver and kidneys, showing the potential to alleviate metabolic pressure and enhance tissue safety. Therefore, the linker optimization strategy is well suited for CDK19 and provides a reference for the radioactive ligands of other nuclear targets.

P2, N=94, Recruiting, Ryvu Therapeutics SA

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

Our results showed that CD24 expression may induce a cellular quiescence-like state and resistance to platinum-based chemotherapeutic agents in ovarian cancer via miR-130a and 301a upregulation. CD24-miR-130a/301a-CDK19 signaling axis could be a prognostic marker for or a potential therapeutic target against ovarian cancer recurrence.

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

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

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.

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.

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.

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.

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.

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

Thus, we have generated a novel PET small molecule with predictive value for prostate cancer. The findings indicate that Ga-CDK19 may merit further evaluation as a predictive biomarker for PET scans in prospective cohorts and may facilitate the identification of molecular types of prostate cancer independent of PSMA.

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.

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.

They synergized with anti-PD-1 and anti-CTLA-4 and led to tumor eradication and immunological memory formation. These studies identify novel allosteric inhibitors with potent synthetically lethal anti-tumor activity.

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.

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.

miR-30c-5p inhibits OvCa progression and reduces the m A level by inhibiting m A reader HNRNPA2B1, thus providing new insights into the m A regulatory mechanism in OvCa.

RVU120 demonstrates a favorable safety profile at the tested dose levels. In a heavily pretreated, unselected all-comer population, disease stabilization was observed in 2 patients. Available data warrant continuation of dose escalation and collection of additional clinical data.

Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2 BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2 BrCa.

This study revealed that hsa_circ_0006692 promoted NSCLC progression via enhancing cell growth, invasion, and metastasis through sponging mir-205-5p, up-regulating the downstream oncogene CDK19 and modulating EMT of lung cancer cells. The circ-0006692/mir-205-5p/CDK19 axis might serve as a prognosis biomarker and target for drugs aimed against NSCLC.

Preliminary evidence of clinical response to RVU120 has been also shown in R/R AML and HR-MDS patients positive for DNMT3A mutations. Further molecular studies in greater number of patients under RVU120 treatment are ongoing and will provide evidence for predictive markers of response to RVU120 in AML.

Meaningful PD activity and clinical efficacy were observed at 50 and 75 mg doses. Enrollment is currently ongoing at 85 mg cohort

These results suggest Hotair indirectly up-regulates CDK19 through sponging miR-222-3p, which enhances the malignant behavior of OC. This provides a further understanding of the mechanism of the occurrence and development of OC.

A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg.

Combining CDK8/CDK19 inhibitors with anti-androgens led to synergistic antiproliferative effects and sensitized androgen-independent cells to bicalutamide...In summary, this study substantially supports recent findings on CDK8/CDK19 in PCa progression. These findings contribute to a better understanding of underlying pro-oncogenic effects which is needed to develop CDK8/CDK19 as a therapeutic target in PCa.

Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.

P1, N=74, Recruiting, Tyligand Bioscience (Shanghai) Limited

To achieve conditional knockout of Cdk8 in Cdk19-deficient background, Cdk19-/- mice were crossed with previously developed mice with floxed Cdk8 (McCleland et al., ibid) and with ROSA tamoxifen-inducible Cre recombinase...The newly developed mice with constitutive Cdk19 and inducible Cdk8 knockout will be used to study the different physiological roles of Mediator kinase, to evaluate the stromal effects of Mediator kinase inhibition on tumor growth and to predict potential side effects of long-term CDK8/19 inhibitor therapy. (Supported by Megagrant 14.W03.31.0020 from the Ministry of Science and Education of the Russian Federation).

BLISS analysis of dual treatment with EGFR TKI neratinib and dasatinib or dovitinib revealed synergistic drug interactions in most lines...Acute response was examined by treating drug-naïve cells with afatinib over 48h, and long-term kinome rewiring was observed by comparing untreated cells to gefitinib- and erlotinib-resistant cell lines...Eight of these kinases (Cdk19, Ddr1, Kalrn, Khk, Mapk3, Pink1, Tnik, Ulk2) appear in both the in vitro and in vivo datasets, indicating a conserved kinome response regardless of method of resistance generation. Overall, integrated kinome profiling in GBM models with defined mutational profiles provides a powerful framework to identify novel therapeutic targets that could significantly alter current treatment paradigms.

Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. Overall, these studies provide rationale for further development of RVU120 in TNBC patients.

In Cohort #4 (75 mg), a R/R AML patient with DNMT3A mutation achieved a Complete Remission (CR) being in disease progression under venetoclax/decitabine treatment...The first patient, with history of early post-transplant relapse, TP53 biallelic mutation and complex karyotype with disease progression under prior treatment with venetoclax/azacytidine, experienced worsening of nausea and vomiting from the first day of study drug administration... RVU120 shows preliminary signs of efficacy in AML and HR-MDS with a tolerable safety profile, including a CR and an ER in patients previously treated with venetoclax combination therapy. Enrollment is ongoing in cohort 4 to gather additional safety data Keywords: AML, MDS, RVU120, SEL120, CDK8/CDK19 inhibitor