P1, N=15, Not yet recruiting, M.D. Anderson Cancer Center

HERV expression following ZNF274 loss induces a double stranded RNA response that reinforces the classical to basal subtype transition. Here, we show ZNF274 is an important epigenetic regulator of cellular plasticity and sensitivity to CDK7 inhibition, presenting a therapeutic liability of PDAC subtype transition that is actionable in the clinic.

Oral administration of GNE-3511 at 20 mg/kg (twice daily) demonstrated significant anti-tumor efficacy and improved survival in both U-87 MG and T98G xenograft/orthotopic mouse models. Collectively, these findings highlight GNE-3511 as a promising lead candidate for the development of GBM therapeutics.

P1/2, N=49, Completed, Carrick Therapeutics Limited | Active, not recruiting --> Completed

P1/2, N=230, Recruiting, Exscientia AI Ltd., a wholly owned subsidiary of Recursion Pharmaceuticals, Inc. | N=165 --> 230

Additionally, CDK7 knockout (KO) and selective inhibitors (YKL-5-124 and samuraciclib) demonstrated potent antitumor activity, effectively suppressing tumor growth in HNSCC patient-derived organoids (PDOs), as well as in both cell line- and patient-derived xenograft (PDX) mouse models with minimal toxicity...These findings highlight CDK7 as a promising therapeutic target for HNSCC. Our study provides strong evidence of the robust antitumor activity of CDK7-selective inhibition in disease-relevant preclinical models, strongly supporting its progression to clinical testing.

P1, N=54, Terminated, Eli Lilly and Company | Phase classification: P1a/1b --> P1

The antifungal activity of SY-1365 was also markedly enhanced in combination with membrane-targeting antifungals. Together, our findings highlight CDK7 inhibitors as valuable tools to study CDK7 function in Cn and as potentially promising antifungals in combination with licensed antifungals.

P2, N=60, Completed, Carrick Therapeutics Limited | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Aug 2025

We verified the effectiveness of our assay by demonstrating that previously known Myc-downregulating compounds (G9 and SY-1365) were successfully identified from a library of bioactive compounds with established biological function...The self-aggregation of Myc and the dissociation of the Myc/Max dimer by C1 promoted Myc degradation. Using a target-NanoLuc fusion strategy in our novel cell-based high-throughput screening system, we identified a molecular glue-like small molecule degrader of Myc.

Continuous culturing of prostate cancer cells with Samuraciclib, a non-covalent ATP-competitive CDK7i, led to outgrowth of resistant cells...Consistent with this, mutation of the homologous residue in CDK12 (D819N) or CDK4 (D99N) promoted resistance to drugs that inhibit these CDKs. Our findings reveal a general mechanism for acquired resistance with obvious implications for patients treated with CDK inhibitors.

Notably, the novel lead compound 8b exhibited approximately 2.5-fold greater potency than roscovitine. Molecular docking studies further supported the experimental findings and provided structural insights for future optimisation of this promising CDK2 inhibitor scaffold.