alvocidib (DSP-2033) / Sumitomo Pharma - LARVOL DELTA

Identification of CDK1 as a Biomarker for the Treatment of Liver Fibrosis and Hepatocellular Carcinoma Through Bioinformatics Analysis. (PubMed, Int J Mol Sci) - "Molecular docking simulations evaluated CDK1's binding affinity with pharmacologically active compounds (alvocidib, seliciclib, alsterpaullone) using AutoDock Vina. The enzyme's dual role in driving tumor progression and reshaping the immune microenvironment positions it as a promising therapeutic target. Computational validation of CDK1 inhibitors provides a rational basis for developing precision therapies against LF-HCC, bridging translational gaps between biomarker discovery and clinical application."

Biomarker • Journal • Fibrosis • Hepatocellular Cancer • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • CDK1

Therapeutic Potential of Flavopiridol in the Suppression of Lung Fibrosis Via CDK9 Inhibition (ATS 2025) - "The CDK9 inhibitor flavopiridol was evaluated in vitro using IPF lung fibroblast cell lines and in vivo in a bleomycin-induced murine model of IPF...In a mouse model of lung fibrosis, systemic administration of flavopiridol attenuated body weight loss, improved survival rates, and reduced fibrotic lesions and collagen deposition, showing superior antifibrotic efficacy compared to the FDA-approved drug nintedanib... Our findings suggest that CDK9 serves as a critical regulator of fibrogenesis in IPF and that inhibiting CDK9 through the use of flavopiridol represents a promising therapeutic strategy. The formulation of a novel method for the pulmonary delivery of flavopiridol presents a potential targeted treatment approach for IPF."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Discovery of flavopiridol as a noncovalent thioredoxin reductase inhibitor through in silico and in vitro approach. (PubMed, Int J Biol Macromol) - "Importantly, surface plasmon resonance (SPR) experiments validated the binding interaction between flavopiridol and TrxR. This study offers valuable insights into the identification and investigation of novel TrxR inhibitors, potentially enhancing the application of flavopiridol as a promising TrxR inhibitor."

Journal • Preclinical • Oncology

Modulation of the cell cycle and inhibition of histone deacetylases by small molecules increase recombinant adeno-associated virus productivity across different HEK293 cell lines. (PubMed, Biotechnol Prog) - "A DoE-based approach also revealed the potential for combining both molecules to enhance rAAV production, exhibiting an additive effect across three different HEK293 derivatives. Consequently, novel functions of M344 and Flavopiridol as enhancers of rAAV production were unraveled, which can be employed to enhance the accessibility of in vivo gene therapy applications."

Journal • Preclinical • Gene Therapies

A pan-cancer analysis reveals the oncogenic and immunological role of insulin-like growth factor 2 mRNA-binding protein family members. (PubMed, Discov Oncol) - "IGF2BPs exhibit significantly high expression in most tumors and are associated with prognosis, pathological stage, mutational status, methylation levels, and the relevant indicators of immunotherapy sensitivity in multiple tumors. Moreover, IGF2BPs may play an oncogenic role by activating common signaling pathways. Therefore, IGF2BPs may be potential prognostic markers for tumor therapy and targets for immunotherapy and drug therapy."

IO biomarker • Journal • Pan tumor • Tumor mutational burden • Microsatellite Instability • Oncology • AMPK • IGF2BP1 • MSI • TMB

NCAPH Promotes the Proliferation of Prostate Cancer Cells Via Modulating the E2F1 Mediated PI3K/AKT/mTOR Axis. (PubMed, Int J Med Sci) - "Notably, combining NCAPH knockdown with an mTOR inhibitor (Everolimus) or a cyclin-dependent kinase inhibitor (Flavopiridol) demonstrated promising anti-tumor effects both in vitro and in vivo. This study highlights the significant pro-tumor role of NCAPH in PCa and suggests its potential as a therapeutic target."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • E2F1 • NCAPH

Genomics-based approach to drug testing in novel patient-derived xenograft models of undifferentiated pleomorphic sarcoma (EORTC-NCI-AACR 2024) - "Alvocidib, abemaciclib, copanlisib and trametinib had the lowest average IC50 values (208 nM, 407 nM, 348 nM and 452 nM respectively). RPPAs to investigate the mechanism behind the synergy of trametinib and infigratinib in UPS cell lines and in vivo experiments aimed at comparison of trametinib and infigratinib combination and doxorubicin (standard of care) efficacy in UPS PDX models are ongoing. Conclusion Trametinib monotherapy or in combination with infigratinib represents a potential novel therapy for UPS patients."

Preclinical • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma

Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia (ASH 2024) - "Relapsed disease has poor prognosis, especially after immunotherapeutic approaches have failed, including blinatumomab (bispecific T cell engager BITE) and chimeric antigen receptor T-cell (CAR-T) therapy...Methods : Venetoclax, alvocidib, S63845 (MCL1i), dexamethasone and tyrosine kinase inhibitors (TKIs) were from Selleckchem...Conclusions : Simultaneous inhibition of BCL-2 and CDK9 represents an effective approach for targeting Ph+, KMT2AR and CD19-/- B-ALL without need for additional DNA-damaging chemotherapy or kinase inhibition. Taken together, this provides strong rationale for the clinical translation of venetoclax combined with alvocidib in patients with poor prognosis ALL, thereby offering a promising novel combination treatment for CAYA."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CDK9 • KMT2A • PRKDC

Flavopiridol Restores Granulopoiesis in an Experimental Model of Severe Congenital Neutropenia (ASH 2024) - "These data provide insight into the mechanism of action of flavopiridol in rescuing defective granulopoiesis in CN. Thus, we described for the first time a therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia."

Hematological Disorders • Neutropenia • Oncology • CD34 • CDK2 • CDK4 • CEBPA • ELANE • SRP54

Flavopiridol restores granulopoiesis in experimental models of severe congenital neutropenia. (PubMed, Mol Ther) - "Flavopiridol also restored granulopoiesis caused by diminished CEBPA expression, a known defective signaling molecule in CN. Thus, we described for the first time a potential therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia."

Journal • Hematological Disorders • Neutropenia • CD34 • CEBPA • ELANE

Flavopiridol: a promising cyclin-dependent kinase inhibitor in cancer treatment. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Future research efforts should focus on refining its therapeutic profile, minimizing toxicity, and investigating synergistic treatment combinations, including those with immunotherapy. Understanding the mechanisms of resistance and discovering predictive biomarkers will be crucial for its effective integration into clinical practice."

IO biomarker • Journal • Review • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Flavopiridol induces cell cycle arrest and apoptosis by interfering with CDK1 signaling pathway in human ovarian granulosa cells. (PubMed, Sci Rep) - "FP reduced cell proliferation and induced apoptosis by inducing mitochondrial dysfunction and oxidative stress, as well as increasing BAX/BCL2 and pCDK1 levels. These results suggest that toxicity to the reproductive system should be considered when FP is used in clinical applications."

Journal • Metabolic Disorders • Oncology • BAX • BCL2 • CDK1

Identification of potential therapeutic targets for systemic lupus erythematosus based on GEO database analysis and Mendelian randomization analysis. (PubMed, Front Genet) - "Simultaneously, molecular docking technology revealed that two compounds, genistein and flavopiridol, have potential therapeutic effects with ISG15, providing new potential drugs for SLE treatment. These discoveries not only enhance our understanding of the pathogenesis of SLE but also provide important clues for developing new treatment strategies."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • DDX58 • IFIH1 • IRF7 • ISG15 • STAT1

Synthetic Approach to Chromone and Flavonoid Piperidine Alkaloids. (PubMed, J Org Chem) - "Consequently, the simultaneous installation of the functionalized phenol group and the exo-methylene group within the piperidine skeleton, permits, not only the easy construction of the chromone or flavonoid cores but also the simultaneous installation of the hydroxyl group with the required cis-orientation. Additionally, the synthetic utility of this novel approach is showcased in the formal synthesis of flavopiridol, rohitukine, and their N-Moc analogues."

Journal

Analysis of the Leishmania mexicana promastigote cell cycle using imaging flow cytometry provides new insights into cell cycle flexibility and events of short duration. (PubMed, PLoS One) - "Our custom-developed masking and gating scheme allowed us to identify elusive G2 cells and to demonstrate that the CDK-inhibitor, flavopiridol, arrests cells in G2 phase, rather than mitosis, providing proof-of-principle of the utility of IFC for drug mechanism-of-action studies. Further, the high-throughput nature of IFC allowed the close examination of promastigote cytokinesis, revealing considerable flexibility in both the timing of cytokinesis initiation and the direction of furrowing, in contrast to the related kinetoplastid parasite, Trypanosoma brucei and many other cell types. Our new pipeline offers many advantages over traditional methods of cell cycle analysis such as fluorescence microscopy and flow cytometry and paves the way for novel high-throughput analysis of Leishmania cell division."

Journal

RNA sequencing identifies lung cancer lineage and facilitates drug repositioning. (PubMed, PeerJ) - "Our results indicated that dinaciclib and alvocidib exhibited similar activity and sensitivity in the neuroendocrine cluster. Also, a lineage factor named KLF5 recognized by inferred transcriptional factors activity could be suppressed by verteporfin."

IO biomarker • Journal • Inflammatory Arthritis • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLF5 • STK11

Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry. (PubMed, Ann Med) - "PAAD with high MCM3 expression was sensitive to c-75, brivanib, flavopiridol and VNLG/124 drugs, with stable molecular docking models. MCM3 is likely to be a critical element in promoting the initiation and growth of PAAD. Flavopiridol may exert its anti-PAAD effect through the interaction between MCM3, classic CDK1 targets in the cell cycle checkpoint and p53 pathway as well as related molecules in other pathways."

Biomarker • Journal • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • CDK1 • MCM3

Flavopiridol inhibits oocyte maturation, reduces oocyte quality and blocks cumulus cell function. (PubMed, Toxicol Lett) - "This may be due to the excessive oxidative stress caused by mitochondrial membrane potential damage and mislocalization. Therefore, when FP is used for cancer treatment, its side effects on the female reproductive system should be seriously considered."

Journal • Infectious Disease • Oncology

Flavopiridol inhibits adipogenesis and improves metabolic homeostasis by ameliorating adipose tissue inflammation in a diet-induced obesity model. (PubMed, Biomed Pharmacother) - "In the mouse model of diet-induced obesity, flavopiridol attenuated obesity-associated adipose tissue inflammation and improved serum lipid profile, glucose tolerance as well as insulin sensitivity. In conclusion, the FDA approved drug flavopiridol could be placed as a potential drug candidate for the treatment of cancer and obesity comorbid patients."

Journal • Genetic Disorders • Inflammation • Obesity • Oncology • CEBPA • FASN • PPARG

Investigating the molecular mechanism of vitexin targeting CDK1 to inhibit colon cancer cell proliferation via GEO chip data mining, computer simulation, and biological activity verification. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Molecular docking revealed a strong interaction between Vitexin and CDK1 (Docking score - 9.497), with molecular dynamics simulations confirming the stability of the Vitexin-CDK1 complex and comparable inhibitory effects to Flavopiridol. Vitexin can inhibit the expression of CDK1/cyclin B proteins in HCT-116 cells, with an IC50 of 58.06 ± 3.07 μmol/L. Vitexin may inhibit colon cancer HCT-116 cell proliferation by suppressing CDK1/cyclin B expression, leading to cell cycle arrest in the G2/M phase."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDK1

Uncovering potential CDK9 inhibitors from natural compound databases through docking-based virtual screening and MD simulations. (PubMed, J Mol Model) - "The first-generation CDK inhibitor Flavopiridol was used as a reference to compare with our novel hit compound as a CDK9 antagonist...They also showed reasonable figures in the predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations as well as in computational cytotoxicity predictions. Therefore, we anticipate that the proposed scaffolds could contribute to developing potential and selective CDK9 inhibitors subjected to further validations."

Journal • Oncology • Solid Tumor

Discovery of colchicine aryne cycloadduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases in breast cancer cells. (PubMed, Bioorg Chem) - "Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner."

Journal • Breast Cancer • Oncology • Solid Tumor • CCNB1 • CCND1 • CDH1 • CDK2 • CDK4 • VIM

Intra-articular injection of an extended-release flavopiridol formulation represents a potential alternative to other intra-articular medications for treating equine joint disease. (PubMed, Am J Vet Res) - "Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • CDK9

Therapeutic potential of flavopiridol in diabetic retinopathy: Targeting DDX58. (PubMed, Int Immunopharmacol) - "Notably, our research demonstrated that flavopiridol modulates the DDX58/NLRP3 signaling pathway, thereby exerting its therapeutic effects in suppressing inflammation and neovascularization in DR. This study unveils groundbreaking therapeutic agents and innovative targets for DR, and establishes a progressive theoretical framework for the application of ubiquitin-related therapies in DR."

Journal • Diabetes • Diabetic Retinopathy • Inflammation • Metabolic Disorders • Retinal Disorders • Targeted Protein Degradation • DDX58 • NLRP3

Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos. (PubMed, PLoS Genet) - "In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous mcl1a compared to vehicle, consist with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CDK9