enitociclib (VIP152) / Bayer, Vincerx - LARVOL DELTA

Preclinical activity of investigational menin inhibitor DSP-5336 (Enzomenib)-based combinations against MLL1-rearranged (MLL-r) or mutant-NPM1 AML models (ASH 2025) - "Previously reported preclinical data showed that treatment with Menin inhibitor (MI),e.g., SNDX-5613 (revumenib) or KO-539 (ziftomenib), disrupts binding of Menin to MLL1/2 and MLL1-FP,leading to reduced MLL1/2 and MLL1-FP target gene expression, as well as induction of differentiationand apoptosis in AML cells expressing MLL-FP or mtNPM1c...Notably, in the cell lines and PD AML cells with MLLr ormtNPM1c AML, in vitro treatment with DSP-5336 in combination with CDK9 inhibitor (CDK9i) AZD4573 orBAY1251152 for 48 to 96 hours induced synergistic apoptosis or loss of viability, as discovered by the ZIPmethod with SynergyFinder...In vivo co-treatment with DSP-5336 and BAY1251152 showedsignificantly greater reduction in AML burden than treatment with each agent alone (p< 0.05), withoutinducing weight loss or other toxicities. These preclinical findings underscore the anti-AML activity of DSP-5336 and its molecular correlates, aswell as demonstrate synergistic in vitro and..."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2 • CASP3 • CD123 • CD33 • CD99 • CDK6 • CLEC12A • FLT3 • HOXA9 • IFNG • IL3RA • ITGAM • KMT2A • MEF2C • MEIS1 • NPM1 • PBX3

The Selective CDK9 Inhibitor VIP152 Overcame Therapeutic Resistance in Mantle Cell Lymphoma (ASH 2023) - "Moreover, VIP152 markedly inhibited the growth of three patient-derived xenograft tumor models, overcoming BTKi resistance (P<0.001), BTKi-venetoclax dual resistance (P<0.01), and BTKi-CAR-T dual resistance (P<0.001). Conclusion These data showed that CDK9 was a promising target for treating MCL and using VIP152 to specifically target it was efficacious in overcoming a variety of therapeutic resistances in MCL."

IO biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CASP3 • CCND1 • MCL1

Targeting CDK9 in KMT2A-Rearranged Infant Leukemia: Evidence for Activity and Drug Synergy with Enitociclib (ASH 2023) - "Enitociclib also potentiated the anti-leukemic effect of chemotherapies for childhood leukemia with the most effective combination observed with doxorubicin (0.01µM IC50 for doxorubicin alone, 0.002µM IC50 when combined with enitociclib) and prednisolone (25µM IC50 for prednisolone only, 0.01µM IC50 in combination). Data from in vitro cytotoxicity assays showed high sensitivity of KMT2Ar infant leukemia cells to enitociclib with IC50 values of 30nM for KMT2Ar cells and 406nM for KMT2A-WT cells. Annexin V/PI staining showed a dose-dependent increase in cells in the late apoptotic stage for KMT2Ar cells after treatment. Target validation assays in KMT2Ar cells showed inhibition of transcriptional elongation by decreased serine phosphorylation by approximately 75% of RNA POL II CTD starting as early as 6 hours after treatment with 0.1µM enitociclib."

Hematological Malignancies • Leukemia • Oncology • Pediatrics • ANXA5 • CD34 • CDK9 • HOXA9 • KMT2A

Orally Effective CDK9 Inhibitor YX0798 for Treating Aggressive Lymphoma (ASH 2024) - "We also showed AZD4573 and enitociclib are safe and effective treatments in preclinical MCL models, and the therapeutics target CDK9. Mechanistically, YX0798 or the commercial competitor led to CDK9 inhibition and primarily resulted in downregulation of short-lived oncoprotein c-MYC and pro-survival protein MCL-1. Ultimately, CDK9 inhibition disrupted the cell cycle and switched cellular metabolism towards oxidative phosphorylation, eventually leading to cell death.ConclusionsTogether, our study demonstrates that YX0798 is an orally bioavailable CDK9 inhibitor with exquisite selectivity and anti-tumor potency that drives transcription reprogramming towards tumor cell killing."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDC37 • HSP90AA1 • MCL1 • MYC

Enitociclib (VIP152), venetoclax and prednisone in relapsed or refractory aggressive non-Hodgkin lymphoma. (PubMed, Br J Haematol) - No abstract available

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Targeting CDK9 inhibits the growth of KMT2A-rearranged infant leukemia and demonstrates synergy with menin inhibition. (PubMed, Blood Neoplasia) - "Enitociclib also potentiates the cytotoxicity of venetoclax in relatively venetoclax-resistant KMT2A-r leukemic cells. Overall, enitociclib has shown measurable in vitro antitumor activity in KMT2A-r infant leukemia and is a rational therapeutic option to explore in future clinical trials."

Journal • Hematological Malignancies • Leukemia • Oncology • HOXA9 • KMT2A • MCL1

Evaluation of two novel Cyclin Dependent Kinase 9 inhibitors for the treatment of Myeloid Cell Leukaemia 1 (MCL1) high Chronic Lymphocytic Leukaemia (IWCLL 2025) - "The CDK9 inhibitor VIP152 has been shown to significantly reduce disease burden and improve overall survival in a murine CLL model (Sher et al, 2022), providing a rationale for the use of CDK9 inhibitors in CLL.We evaluated two novel selective CDK9 inhibitors, AU4-53 and AU11-8, for the treatment of CLL and hypothesised that patients with high MCL1 expression will be particularly responsive and that patients with high BCL2 and MCL1 expression may benefit from combination therapy with venetoclax. Peripheral blood expression of BCL2, BCL-XL and MCL1 was measured in primary CLL cells by multi-colour flow cytometry. The novel selective CDK9 inhibitors AU4-53 and AU11-8 show in vitro efficacy in CLL, implicating targeted inhibition of this kinase as an exciting therapeutic strategy for the treatment of MCL1 high CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BCL2L1 • CD40LG • CDK9 • MCL1 • TLR9

Phenotypic screening converges on CDK9 inhibition as a therapeutic strategy in translocation renal cell carcinoma. (PubMed, bioRxiv) - "These effects were recapitulated by the CDK9-selective inhibitor enitociclib, which downregulated TFE3 targets and suppressed tRCC cell growth. Our findings nominate CDK9 inhibition as a therapeutic strategy in tRCC and demonstrate the utility of mechanism-informed phenotypic screening for challenging targets."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • TFE3

Cyclin-dependent kinase 9 inhibitors as oncogene signaling modulators in combination with targeted therapy for the treatment of colorectal cancer. (PubMed, bioRxiv) - "CDK9 inhibitors show promising activity against patient-derived models of CRC. MAPK signaling is particularly suppressed by CDK9 inhibitors. Combining CDK9 inhibitors and targeted therapy against MAPK signaling pathway may be a viable strategy worthy of further investigation preclinically and clinically."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CDK9

Hepatitis B surface antigen is upregulated by HIV Tat in an HIV-hepatitis B virus co-infection model system. (PubMed, Microbiol Spectr) - "This could be rescued by CDK9 inhibition with BAY-1251152...Our findings have implications for interventions aiming to cure HIV through latency reversal, as these interventions can specifically increase the Tat protein. Future exploratory treatment strategies, such as Tat inhibitors, could play a role in the management of people with HIV and HBV at high risk of liver disease."

Journal • Hepatitis B • Hepatocellular Cancer • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor

YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma. (PubMed, Blood Adv) - "We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. Furthermore, YX0798 has the potential to be used in combination therapy with clinical agents to improve treatment efficacy. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDC37 • HSP90AA1 • MCL1 • MYC

Study of VIP152, Venetoclax, and Prednisone (VVIP) in Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Dec 2025

Trial completion date • B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • ALK • BCL2

Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma. (PubMed, Blood Neoplasia) - "Additionally, enitociclib demonstrated synergistic effects with several anti-MM agents, including bortezomib, lenalidomide, pomalidomide, and venetoclax. These results suggest that enitociclib may represent a promising therapeutic option for the treatment of MM, either as a single agent or in combination with other anti-MM agents."

Journal • Preclinical • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • CDK9 • MCL1 • MYC • PCNA

High-throughput screening reveals novel synergistic drug combinations for metastatic castration-resistant prostate cancer (AACR 2025) - "Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, with patients often developing resistance to androgen receptor (AR)-axis-targeted therapies such as Abiraterone and Enzalutamide...These results guided the development of a novel triple combination therapy to simultaneously target CDK9-regulated productive RNA polymerase II phosphorylation (Enitociclib), BRD4-mediated epigenetic remodeling (Pelabresib), and pro-survival BcL-xL (Navitoclax)...These findings provide a strong rationale for clinical development of multi-drug targeted combination regimens to overcome AR-V7-driven resistance and deliver durable responses with reduced toxicity for mCRPC patients with limited treatment options. Our approach also highlights the power of HTS to unbiasedly innovate synergistic therapies while uncovering critical biological mechanisms underlying cancer drug resistance."

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BCL2L1 • BRD4 • CASP3 • CASP7 • CDK9

Dysregulating transcription and epigenetic remodeling using dual BRD4 and CDK9 inhibition in pancreatic ductal adenocarcinoma (AACR 2025) - "Here, we show preclinical evidence that combination treatment of VIP152 and ZEN3694 synergistically dysregulates PDAC transcription and remodels the epigenomic landscape. Future directions will include exploring Myc amplified subtype specific selectivity and in vivo validation of toxicity and efficacy."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRD4 • MYC

Drug discovery of potent and specific CDK9 protein degraders for the treatment of refractory lymphomas (AACR 2025) - "To construct CDK9 PROTACs, we adopted our identified CDK9is, clinical candidates AZD4573 and VIP152, conjugating with E3 ligands via diverse linkers for comparison studies. Through rational drug design and structure-based chemical optimization, YX0798 was discovered as a novel CDK9i with high binding affinity, cellular potency, target specificity, and favorable PK properties. Several promising potent and specific CDK9 degraders such as YX0597 have been identified. YX0597 is a bona fide CDK9 degrader highly effective against various resistant MCL cells, induces cell apoptosis and suppresses the tumor growth in vivo at a very low dosage in a PDX mouse model with dual resistance to BTKi and CAR-T, indicating its potential for the treatment of refractory lymphomas including resistant MCL."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CASP3 • CDK9 • MCL1 • MYC

Organoid-based drug screening identifies CDK9 as a target for stratified treatment of high-grade serous ovarian cancer (AACR 2025) - "To explore the CDK9i responses in HGSC, we profiled 18 organoid cultures against selective CDK9i (AZD4573, VIP-152, NVP-2 and KB-0742). For instance, expression of phosphodiesterase 3B (PDE3B) was correlated with CDK9i resistance (Pearson r = -0.744, p<0.001), while expression of ERBB3 was correlated with increased CDK9i sensitivity (Pearson r = 0.841, p<0.0001).Taken together, we demonstrate the application of an HGSC organoid biobank for identifying patient-specific targets, exceptional responder groups and potential CDK9i sensitivity biomarkers in HGSC. Results of this project could serve as a basis for designing a molecularly stratified CDK9 inhibitor-focused clinical trial in refractory HGSC patients."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDK9 • ERBB3 • MYC

Targeting transcriptional regulation using CDK7 and CDK9 inhibition as a novel combination therapy in fibrolamellar carcinoma (AACR 2025) - "Here, we show FLC has an increase in phosphorylated RPB1 specifically at s5 and s7, and a unique sensitivity to CDK7 inhibition with SY5609. The addition of CDK9 inhibition using VIP152 is synergistic at downregulating FLC specific driver genes and decreasing activated RPB1 and viability. Ongoing work is validating this combination in animal models to assess toxicity and in vivo efficacy."

Combination therapy • Biliary Cancer • Cholangiocarcinoma • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CDK7 • DNAJB1 • LINC00473 • PRKACA

Design, synthesis and bio-evaluation of 2,5-disubstituted thiazole derivatives for potential treatment of acute myeloid leukemia through targeting CDK9. (PubMed, Bioorg Chem) - "Among them, compound 24 displayed the best antiproliferative activity against MOLM-13 cells with an IC50 value of 0.034 μM, which was comparable to the positive drug (BAY1251152, IC50 = 0.031 μM)...Finally, further studies of compound 24 about molecular docking, molecular dynamics simulations and ADMET prediction were investigated. Collectively, compound 24 deserves further structural optimization and development for the treatment of acute myeloid leukemia."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK9

Study of VIP152, Venetoclax, and Prednisone (VVIP) in Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=130 ➔ 8 | Trial completion date: Jul 2029 ➔ Jun 2025

Enrollment change • Trial completion date • B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • ALK • BCL2

Study of VIP152, Venetoclax, and Prednisone (VVIP) in Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=130 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Jul 2029 | Trial primary completion date: Mar 2025 ➔ Jul 2024

Trial completion date • Trial primary completion date • B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • ALK • BCL2

Study of VIP152, Venetoclax, and Prednisone (VVIP) in Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=130 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • ALK • BCL2

VNC-152-101: Phase I Dose Escalation Study for VIP152 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=110 | Completed | Sponsor: Vincerx Pharma, Inc. | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Monotherapy • Trial completion • Oncology • MYC

Vincerx…Provides Pipeline and Corporate Updates (GlobeNewswire) - P1/2 | N=130 | NCT05371054 | P1 | N=110 | NCT02635672 | Sponsor: Vincerx Pharma, Inc. | "Enitociclib...is currently being evaluated in a Phase 1 dose-escalation study in combination with venetoclax and prednisone....As of September 2024, the study reported four partial responses (PRs) in seven patients (57% overall response rate), including one patient with double hit lymphoma (DH-DLBCL) and three patients with PTCL....The study is currently enrolling in the third dose level (enitociclib 30 mg [efficacious dose] and venetoclax 600 mg) with two patients enrolled to date. Additionally, in a separate Phase 1 study of enitociclib as a monotherapy (30 mg), one patient with transformed follicular lymphoma achieved a metabolic PR. As of September 2024, this patient remains on enitociclib monotherapy after more than 26 months. Overall, these clinical results continue to show the promising safety, tolerability, and efficacy of enitociclib for the treatment of relapsed/refractory lymphoma."

P1 data • Trial status • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Peripheral T-cell Lymphoma

Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development. (PubMed, Bioorg Med Chem Lett) - "YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900)."

Journal • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor