As the second most malignant neoplasm in the world, colorectal cancer (CRC) still needs the novel treatment strategy urgently. Cyclin-dependent kinase 2 (CDK2) has been identified as a potential therapeutic target in CRC research, but the development of CDK2 inhibitors still faces significant challenges. This study was to investigate the efficacy and underlying mechanisms of licoisoflavone A (LA) in targeting CDK2. HCT116 and SW480 human CRC cells were used to evaluate the in vitro anti-CRC activity and CDK2 regulation effect of LA by flow cytometry and Western blot analysis. Molecular docking and CDK2 knockdown cell models were used to investigate the direction interaction between LA and CDK2. Patient-derived CRC organoids and tumor-bearing mice were used to verify the anti-CRC activity and mechanism of LA. As a result, LA significantly inhibited cell proliferation and induced G1/S phase arrest in HCT116 and SW480 cells. LA had direct interaction with CDK2, and not only inhibited the formation of the CDK2/cyclin E1 complex, but also suppressed its kinase activity through the upregulation of p27, thereby inhibiting Rb phosphorylation and arresting the cell cycle in the G1 phase. Moreover, LA exerted anti-CRC effect in CRC organoids and the subcutaneous xenograft tumor mode without evident toxic effects. LA inhibits CRC cell proliferation through targeting the CDK2-Cyclin E1 axis-mediated cell cycle transition. Our research provides compelling evidence that LA may serve as a potential agent for the treatment of CRC, and also provides a rationale to design novel CDK2 inhibitors.

2025-10-01·BIOORGANIC CHEMISTRY

Design, synthesis, biological and computational evaluation of novel S/N-glycerolyl and peptide-conjugated [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent CDK2 inhibitors for anticancer therapy

Article

作者: El-Sayed, Heba A ; Nagy, Ibrahim M ; Abdel-Rahman, Adel A-H

Targeting Cyclin-Dependent Kinase 2 (CDK2) remains a critical strategy in anticancer drug discovery. This study unveils a highly promising series of novel [1,2,4]triazolo[1,5-a]pyrimidine (TP) derivatives, achieved through innovative S/N-glycerolylation and peptide conjugation strategies. We report the rational design, efficient multi-step synthesis (yields up to 85 %), and comprehensive biological and computational evaluation. Notably, peptide conjugate 14c emerged as an exceptionally potent and selective lead, exhibiting outstanding anticancer activity against MCF-7 (IC₅₀ = 0.7 μM), HCT-116 (IC₅₀ = 1.1 μM), and MGC-803 (IC₅₀ = 1.5 μM) cell lines, coupled with remarkable selectivity over non-cancerous HEK293 cells (SI = 22.4). Mechanistic validation confirmed 14c as a superior CDK2 inhibitor (IC₅₀ = 0.21 μM, ∼2-fold more potent than roscovitine) with excellent kinase selectivity (S₁₀ = 0.13). This potent inhibition effectively induced G1 cell cycle arrest (68.7 % at 0.7 μM), Rb dephosphorylation (75 % reduction), and significant apoptosis (38.5 %). Compound 14c demonstrated high metabolic stability in human liver microsomes (t½ = 68.5 min, CLint = 8.5 mL/min/kg), supporting its potential for favorable pharmacokinetics. Molecular docking and extensive 100 ns MD simulations revealed a stable, high-affinity binding mode (Kd ∼175-207 nM), elucidating the structural basis for its efficacy. These findings highlight peptide conjugate 14c as a breakthrough lead compound, demonstrating significant promise for development into a novel, selective CDK2- targeted anticancer therapeutic.

2025-09-11·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2

Article

作者: Sathappa, Murugappan ; Liang, Tong ; Paul, Atanu ; Chen, Dapeng ; Enerson, Brad ; Aversa, Robert J. ; Sawant, Rupa ; Breitkopf, Susanne B. ; Growney, Joseph D. ; Zheng, Xiaozhang ; Li, Kunhua ; Williams, Juliet ; Howarth, Charles ; Yang, Annan ; Kwiatkowski, Nicholas P. ; Collier, Philip N. ; Sharma, Kirti ; Ford, Melissa ; Su, Lijing ; Weiss, Matthew

Cyclin-dependent kinase 2 (CDK2) plays an important role in cell cycle regulation and has emerged as a compelling target for the treatment of cancer, largely because of its potential to overcome the resistance associated with CDK4/6 inhibition. Efforts to develop CDK2 inhibitors have historically proven challenging due to undesirable safety profiles associated with inhibiting off-target CDK isoforms. Herein, we describe the structure-guided discovery of a series of orally bioavailable and selective degraders of CDK2. Degrader 37 demonstrated improved phenotypic selectivity compared to a clinical CDK2 inhibitor, with greater specificity for disease-relevant cyclin E1 (CCNE1)-amplified cancer cells vs nonamplified cohort. The antitumor activity of 37 in mice bearing CCNE1-amplified HCC1569 tumors correlated with sustained >90% degradation of CDK2 and sustained 90% inhibition of Rb phosphorylation.

项与 CDK2 inhibitors(University of Colorado Boulder) 相关的新闻（医药）

2025-08-25

·EndPoints

MannKind to buy scPharmaceuticals for up to $360M; Arnatar launches with $52M

Plus, news about Vaxxas, Mid-Atlantic BioTherapeutics, Incyclix Bio and Invivyd: 🫀 MannKind to buy scPharmaceuticals: The Connecticut biopharma is paying $5.35 per share upfront in cash, plus a potential milestone payment of up to $1.00 per share. The deal gives scPharmaceuticals an equity value of $303 million upfront or $360 million total if the CVR is achieved. The FDA in 2022 approved scPharmaceuticals’ drug-device product Furoscix for certain types of heart failure. MannKind said it would have to pay about $81 million to get out of a credit facility that scPharmaceuticals had inked with Perceptive Advisors . Blackstone is helping fund the acquisition as part of an amendment to a financing agreement earlier this month. MannKind’s stock $SCPH was down about 5% on Monday morning. — Kyle LaHucik 🔬There’s a new RNA medicines biotech: Arnatar Therapeutics, a San Diego biotech founded by former Ionis leaders, launched Monday with a pipeline of RNA medicines for cardio metabolic, liver, kidney and CNS diseases. The company unveiled a $52 million Series A, though it said the round closed last year. Its candidates include Phase 1-stage ART101 for hypertension and ART4, an antisense oligonucleotide for Alagille syndrome that’s been granted orphan and rare pediatric disease designations. — Kyle LaHucik 🩹 Vaxxas raises about $58M for its needle-free vaccine tech: The biotech secured about 90 million Australian dollars to boost production of its high-density microarray patch for “market readiness.” The needle-free vaccine technology has so far been administered to over 750 participants in clinical trials and has shown robust immune response, according to Vaxxas. The funding marks one of this year’s largest financings for a private biotech in Australia. — Alexis Kramer 💰 Mid-Atlantic BioTherapeutics to get up to $50M: Legend Innovation Life Science Fund said Saturday that its planned investment will support Mid-Atlantic’s development of new “anti-aging” drugs for neurological diseases and cancer. Mid-Atlantic should expect the first funding tranche in the third quarter of this year before it begins a Phase 3 trial for its viral encephalitis drug in 2026. — Alexis Kramer 💸 Incyclix Bio extends Series B with $11.3M: The company is working on a CDK2 inhibitor that’s headed to a Phase 1/2 trial, with the help of the new funding. The extension’s investors include Eshelman Ventures, Eli Lilly, Pharmacosmos and Cape Fear BioCapital. — Jaimy Lee 🏷️ Invivyd ended up raising $57.5 million in its public offering, up from the $50 million it sought. — Jaimy Lee

疫苗上市批准并购临床3期

100 项与 CDK2 inhibitors(University of Colorado Boulder) 相关的药物交易

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