CDK7 (Cyclin Dependent Kinase 7)

Accordingly, co-targeting CDK7, which regulates CDK2, CDK4/6, and ERα, additively impacted cell fitness. Collectively, these data reveal a complex, multitiered response to CDK4/6 inhibition, with implications for therapeutic efficacy.

Compared with either drug alone, BS-181-AmB combination therapy provided greater protection against Cn infection in a wax moth model (p ≤ 0.032) and extended survival of Cn-infected mice. These findings demonstrate that CDK7 inhibitors, already of interest as anticancer agents, could be repurposed to prevent or treat opportunistic fungal infections in cancer patients when combined with licensed antifungals limited by either toxicity or resistance.

Both genetic knockdown and pharmacological inhibition of PSMD14 recapitulate EB's effects, confirming its essential role in leukemia cell survival and proliferation. Collectively, these findings uncover a previously unrecognized PSMD14-AKT1/CDK4 regulatory axis in leukemia and position EB as a promising chemical probe and lead compound for the development of targeted covalent inhibitors against oncogenic DUBs.

Reference inhibitors (osimertinib-EGFR, ibrutinib-BTK, THZ1-CDK7, and THZ531-CDK12) reproduced the expected geometries and served as internal controls. Although no quantitative affinity was inferred, the consistent geometric feasibility supports their potential as structural templates for covalent-binding natural scaffolds. These results provide a qualitative, structure-based rationale for further chemoproteomic and enzymatic validation of NP-derived or hybrid compounds as potential leads in cancer therapy, expanding covalent chemical space beyond existing synthetic scaffolds.

Furthermore, we enumerate several identified RIPK1-targeted inhibitors with potential for cancer therapy. Although RIPK1 has been proposed as a potential anticancer target, there are still great opportunities and challenges that require further investigation.

We then found that inhibition of CDK7 can combine with other drug candidates to increase the therapeutic response in FLC cells. Taken together, this suggests CDK7 is a promising target for future treatment in human FLC.

COP may be a natural inhibitor for AKT1, GSK3B, CASP3, TNF and CCND1. COP represses PI3K/AKT pathway to suppress the progression of bladder cancer.

By regulating key oncogenes, SEs represent promising therapeutic targets. Emerging strategies-such as BET inhibitors, CDK7/9 inhibitors, and rational drug combinations-effectively disrupt SE-driven transcriptional programs and show potential to overcome treatment resistance in these cancers.

Identifying molecular drivers of resistance and matching patients to targeted therapies will be essential to optimize outcomes. Continued efforts toward biomarker-based treatment selection and rational sequencing strategies are expected to refine post-CDK4/6i management.

Immunohistochemical analysis showed that capsaicin co-treatment decreased AKT1 (P3: 16.33 ± 0.69 vs. P2: 19.75 ± 0.56) and MAPK1 expression (P3: 13.83 ± 0.61 vs. P2: 20.00 ± 0.34), with a statistically significant reduction in MAPK1 expression (p < 0.05). Capsaicin demonstrated a protective effect by reducing liver damage and downregulating AKT1 and MAPK1 expression in mice with aflatoxin B1-induced hepatotoxicity.

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.

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.