dinaciclib (MK-7965) / Ligand, Merck (MSD) - LARVOL DELTA

CDK9 inhibition enhances apoptosis of TP53 mutated AML when combined with standard chemotherapy (AACR 2025) - "Here we test dinaciclib, a multi-CDK and potent CDK9 inhibitor, alone and with azacitidine and venetoclax to demonstrate that CDK9 inhibition as monotherapy and in combination leads to apoptosis in TP53 mutated AML. To determine the effect of inhibiting CDK9 on the cytotoxicity of AML and normal cells, we treated p53 mutated AML cell lines (THP1, NOMO1, and U937), wild type (WT) p53 AML cell lines (MV4-11 and HL-60) and peripheral blood mononuclear cells (PBMCs) from healthy donors with azacitidine, venetoclax, and dinaciclib. We have shown that the addition of a CDK9 inhibitor to azacitidine and venetoclax results in enhanced cytotoxicity of mutant p53 and WT p53 AML cell lines at low nanomolar concentrations. These results suggest that inhibition of CDK9 sensitizes AML cells independently of TP53, with less pronounced cytotoxicity in normal PBMCs of healthy donors. We plan to further examine the effect of CDK9 inhibition using a highly selective CDK9 inhibitor and..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • GLI2 • PARP1

Suppressing liver metastasis growth by inducing the endogenous expression of the tumor suppressor miR-34a by small synthetic molecules (AACR 2025) - "However, when validating these compounds, only 6 (AT7519, A-674563, BBI503, PCM0240249, KRIBB and SB273005) out of 9 compounds that were tested -induced miR-34a promoter activation and only 2 (AT7519 and A-674563) out of the 6, also caused miR-34a secretion from HepG2, a human hepatoblastoma cell line. Induction of miR-34a using small synthetic molecules is a novel therapeutic approach to eradicate CRC liver metastasis."

Late-breaking abstract • Breast Cancer • Colorectal Cancer • Gastric Cancer • Hepatoblastoma • Melanoma • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • MIR34A

The use of human small intestinal organoids as a preclinical screening tool to assess gastrointestinal toxicity induced by CDK inhibition (AACR 2025) - "All intestinal lineages were present in the organoids and resembled the frequency of linage observed in vivo.The effect of several clinically available CDKIs, such as Dinaciclib, Palbociclib and Abemaciclib, some of them known to induce GI toxicity were assessed. Whereas Palbociclib was the least toxic compound within the human organoid assay, reflecting clinical data that shows the lowest incidence of severe diarrhea.We conclude that organoids are a predictive preclinical model that can be used to identify potential on-target, off-tissue GI toxicities induced by novel therapeutics such as CDKIs. Toxicity and mechanism of action (MOA) can all be addressed in vitro to potentially reduce in vivo experimentation."

Preclinical • Hematological Malignancies • Oncology

Identification of Dinaciclib and Ganetespib as anti-inflammatory drugs using a novel HTP screening assay that targets IFNγ-dependent PD-L1. (PubMed, Front Immunol) - "We discovered that in addition to the known JAK inhibitors Ruxolitinib and Baricitinib, Dinaciclib, a CDK1/2/5/9 inhibitor, and Ganetespib, a Hsp90 inhibitor, significantly inhibit both PD-L1 and CXCL10 expression in the model cells. These drugs also significantly inhibited delayed-type hypersensitivity (DTH) in-vivo in an inflammation mouse model. Our novel screening platform can therefore be used in the future to identify novel immunomodulators and pathways in cancer and inflammation, expanding therapeutic horizons."

IO biomarker • Journal • Immunology • Oncology • CDC37 • CDK1 • CXCL10 • IFNG

Inhibition of pyrimidine synthesis and the cell cycle in mesothelioma (AACR 2025) - "BAY2402234 is an extremely potent inhibitor of cell growth in multiple mesothelioma cell lines and 59-1,881 times more potent than brequinar; 2) BAY2402234 and dinaciclib act synergistically, suggesting an interaction between pyrimidine biosynthesis and one or more of the following CDKs: CDK1, CDK2, CDK5, and/or CDK9; and 3) BAY2402234 results in increased PD-L1 expression and increased cytokine pathway mRNA expression, suggesting the potential for enhancement of immune checkpoint blockade."

IO biomarker • Mesothelioma • Oncology • Solid Tumor • CCNA1 • CCND1 • CDK1 • CDK2 • CDK9 • CDKN1A • PD-L1

CanSeer: a translational methodology for developing personalized cancer models and therapeutics. (PubMed, Sci Rep) - "To exemplify, three use cases involving paired samples, unpaired samples, and cancer samples only, of lung squamous cell carcinoma (LUSC) patients are provided. CanSeer reveals the effectiveness of repositioned drugs along with the identification of several novel LUSC treatment combinations including Afuresertib + Palbociclib, Dinaciclib + Trametinib, Afatinib + Oxaliplatin, Ulixertinib + Olaparib, etc."

Journal • Preclinical • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma

High-throughput drug repositioning identifies dinaciclib as a potent osteosarcoma inhibitor (AACR 2025) - "This study identifies Dinaciclib as a potent inhibitor of osteosarcoma, with additive cytotoxicity when combined with the clinically relevant Gemcitabine+Docetaxel regimen. These findings, coupled with prior evidence of Dinaciclib's efficacy in reducing metastatic burden in OS patient-derived xenograft models, highlight its potential as part of a triple combination therapy. This research underscores the value of high-throughput drug repurposing in identifying innovative treatment strategies for osteosarcoma and supports further preclinical and clinical evaluation of Dinaciclib to improve outcomes for patients with metastatic or treatment-resistant disease."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CDK1

S0826: Dinaciclib in Treating Patients With Stage IV Melanoma (clinicaltrials.gov) - P2 | N=72 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Cutaneous Melanoma • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor

A probe-based target engagement assay for kinases in live cells. (PubMed, Mol Cell Proteomics) - "Comparing intracellular kinase profiles of the marketed drug Dasatinib and the tool compound Dinaciclib with the lysate-based kinobeads assay revealed excellent agreement in rank-order of binding. Dinaciclib showed a systematic shift to higher IC50s suggesting that intracellular co-substrate concentrations, cell penetration of the compound as well as kinase localization and complexes in live cells influence target profiles. Further, we show that sepiapterin reductase SPR and Multidrug Resistance Protein 1 ABCC1 are off-targets of kinase inhibitor scaffolds with potential implications on efficacy and safety."

Journal • ABCC1

Dual inhibition of PLK1 and multi-CDKs: A novel approach for the treatment of adrenocortical carcinomas (Sarcoma-RC 2025) - "Here, we tested the efficacy of 1) the polo-box domain (PBD)-targeting PLK1 inhibitor (PLK1i) Poloxin and the kinase domain (KD)-targeting PLK1i Plogosertib; 2) the CDK1/2 inhibitor (CDKi) Dinaciclib; 3) the combination of Plogosertib and Dinaciclib. Legal entity responsible for the study The authors. Funding Has not received any funding."

Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CDK1 • MUC1 • PLK1

Dinaciclib Interrupts Cell Cycle and Induces Apoptosis in Oral Squamous Cell Carcinoma: Mechanistic Insights and Therapeutic Potential. (PubMed, Int J Mol Sci) - "In conclusion, these findings highlight Dinaciclib's therapeutic promise in OSCC by simultaneously disrupting cell cycle progression and inducing apoptosis. These results support further exploration of Dinaciclib as a viable monotherapy or combination treatment in OSCC and other HNSC subtypes to improve patient outcomes."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CA9 • CASP3

Phytoflavonoids as alternative therapeutic effect for melanoma: Integrative Network pharmacology, molecular dynamics and drug-likeness profiling for lead discovery. (PubMed, Comput Biol Chem) - "Based on potency and drug-ability, we have selected 'CDK1-naringenin' with the standard drug complex, 'CDK1-dinaciclib,' for molecular dynamic simulation at 100 nanoseconds using GROMACS 2020 software. Based on potency (average docking score: 8.35 kcal/mol.), physicochemical properties (obeyed Lipinski rule of five), toxicity (class-IV), fifty percent lethal dose (2000 mg/kg), bioavailability (0.55), drug-likeness score (0.82), along with ideal pharmacokinetics profiles and higher protein-ligand stability, naringenin is considered as a potential and non-toxic anticancer candidate to be used for melanoma as alternative or complementary agent. The integrative and systematic analyses not only highlight the potential of phytoflavonoids but also select the potential lead from the library within limited resources to accelerate the current anticancer drug discovery process."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • CDC25B • CDK1 • GNRP

EXPLORING THE SYNERGISTIC IMPACT OF DINACICLIB AND AFATINIB AS A NOVEL THERAPEUTIC STRATEGY IN GASTRIC CANCER (DDW 2025) - No abstract available

Gastric Cancer • Oncology • Solid Tumor

Investigating resistance to 5-Azacytidine and Venetoclax in PDX models of MDS/AML. (PubMed, Front Oncol) - "Progressing myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) is an indication for hypomethylating therapy (HMA, 5-Azacytidine (AZA)) and a BCL2 inhibitor (Venetoclax, VEN) for intensive chemotherapy ineligible patients. There exist subtle genetic and cytological changes between primary and PDX-AML samples however, the PDX models retain therapy resistance observed in patients. Based on in vitro testing and in vivo validation in PDX models, Panobinostat and Dinaciclib are very promising candidate agents that overcome dual VEN + AZA resistance."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors. (PubMed, Med) - "The findings suggest a strategy for cancer treatment based on synthetic lethality."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CDK1 • CDKN1A • TACC2

Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer. (PubMed, Adv Sci (Weinh)) - "Combination of CDK2 inhibitors in clinical trials (Dinaciclib or PF-07104091) and lenvatinib markedly suppressed growth of xenograft tumors from the lenvatinib-resistant patient. The findings support the combination therapy strategy of lenvatinib and CDK2 inhibitor for lenvatinib-resistant ATC patients with high CDK2 expression."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • CDK2 • FBXW7 • RACK1

The Cdk inhibitor dinaciclib as a promising anti-tumorigenic agent in biliary tract cancer. (PubMed, Cancer Biol Ther) - "Additionally, dinaciclib affects different cell growth regulators like EGFR and STAT3 on gene and protein level, thus decreasing tumor growth. In summary, our study indicates that dinaciclib acts as a promising anti-tumorigenic agent in 2D and 3D in vitro BTC models and thus encourages further investigation."

Journal • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CDK1 • EGFR • MCL1 • STAT3

Inhibition of Cyclin-Dependent Kinase 9 Rapidly Induces Apoptosis in Acute Lymphoblastic Leukemia and Shows Synergistic Activity with BH3-Mimetics (ASH 2024) - "Using the multi-CDK inhibitor dinaciclib, which targets CDK1, 2, 5 and 9, and the specific CDK9 inhibitor AZD4573, we analyzed the effects of both inhibitors in a series of ALL cell lines (BCP-ALL n=10, T-ALL n=6) and primary, patient-derived xenograft (PDX) samples (BCP-ALL n=15, T-ALL n=9)...Based on this, we investigated combinatorial inhibition of CDK9 (AZD4573) together with inhibitors of BCL-2 or BCL-XL (venetoclax, A-1331852, AZD4320) using dose-response matrix analyses and found enhanced cell death and synergistic activity for both combinations...However, intrinsic insensitivity due to dysbalanced protein levels of pro-survival proteins might limit efficacy. Combining CDK9 inhibition with inhibitors of the anti-apoptotic molecules BCL-2/BCL-XL significantly enhances cell death, thus overcoming insensitivity and providing an effective, novel therapeutic anti-ALL strategy to be further evaluated for clinical application."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • BCL2L1 • CASP3 • CDK1 • CDK9 • MCL1

Targeting FOXK2 signaling in breast cancers with FOXK2 amplification/overexpression and PIK3CA oncogenic mutations: a promising therapeutic strategy? (SABCS 2024) - "Inhibiting FOXK2 expression also sensitized breast cancer cells to frontline chemotherapy agents, including doxorubicin, 5-fluorouracil, and etoposide in vitro. These findings provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis. The combination of PIK3CA and CCNE2/CDK2 inhibition by alpelisib and Dinaciclib offers a potential therapeutic strategy for breast cancer with FOXK2 overexpression and PIK3CA oncogenic mutation."

Breast Cancer • Oncology • Solid Tumor • CCNE2 • ER • PIK3CA

CDK9 Inhibition Sensitizes TP53 Mutated AML to Standard Chemotherapy (ASH 2024) - "Here, we combine dinaciclib, a potent CDK9 inhibitor, with standard azacitidine and venetoclax to demonstrate inhibition of CDK9 is an effective approach to inducing apoptosis in TP53 mutated AML.Methods : To determine the effect of inhibiting CDK9 on apoptosis of p53 mutated AML, we treated both p53 mutated AML cell lines, THP1, NOMO1, and U937, and wild type (WT) p53 cell lines, MV4-11 and HL-60, with azacitidine, venetoclax, and dinaciclib, as single-agents and in combination. This action was less pronounced in normal PBMCs. We have ongoing experiments testing this drug combination on normal human CD34+ cells to better determine a therapeutic window to maximize apoptosis in leukemia cells while causing the least cytotoxicity in normal human cells, which should lead to validation studies in vivo."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BIRC5 • CASP3 • CD34 • GLI2 • MCL1 • PARP1

The CDK12-BRCA1 signaling axis mediates dinaciclib-associated radiosensitivity through p53-mediated cellular senescence. (PubMed, Mol Oncol) - "In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12-BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRCA1 • CDK12 • TP53

Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K. (PubMed, RSC Chem Biol) - "This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the de novo design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation in cancers associated with dysregulated cyclin K activity."

Journal • Oncology • Targeted Protein Degradation • CDK12 • DDB1

INHIBITION OF CYCLIN-DEPENDENT KINASE 9 LEADS TO RAPID AND EFFECTIVE APOPTOSIS INDUCTION IN B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (SIOP 2024) - "Interestingly, we identified strong activity of the pan-CDK inhibitor dinaciclib...We observed a dose-dependent reduction of RNA polymerase II (RNAP-II) activity and decreased expression of downstream pro-survival proteins c-MYC, BCL-XL and MCL-1, pointing to cell death induction via the inhibition of CDK9. In line with these observations, CDK9 inhibition with the specific inhibitor ADZ4573 also resulted in rapid apoptosis induction with caspase-3/7/8 activation and PARP cleavage, along with decreased RNAP-II phosphorylation and MCL-1 protein expression.Conclusions Taken together, we identified strong anti-leukemia activity by CDK9 inhibition characterized by rapid and effective cell death induction in BCP-ALL cell lines and PDX samples belonging to various different subtypes, warranting further pre-clinical evaluation."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2L1 • CASP3 • CASP7 • CASP8 • CDK9 • MCL1 • MYC

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

Southwest Oncology Group S0826: A phase 2 trial of SCH 727965 (NSC 727135, dinaciclib) in patients with stage IV melanoma. (PubMed, Cancer) - P2 | "This multicenter, US National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1-year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent."

Journal • Metastases • P2 data • Hematological Disorders • Melanoma • Neutropenia • Oncology • Solid Tumor