enitociclib (VIP152) / Bayer, Vincerx - LARVOL DELTA

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

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

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

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

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

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

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

Enitociclib overcomes resistance in mantle cell lymphoma [Google translation] (IM Medico) - "MD Anderson Cancer Center researchers have conducted the first in vitro and in vivo study of enitociclib in mantle cell lymphoma , finding that twice-weekly intravenous treatment reduced the growth of a human leukemic cell line grafted into mice. Treated animals survived longer, without weight loss or signs of systemic toxicity. Remarkably, enitociclib showed a similar antitumor effect in mice bearing xenografts from patients resistant to BTK inhibitors, or with dual resistance to these agents and venetoclax or to CAR-T therapy targeting the CD19 molecule....'In some of these resistant cell lines, enitociclib induced apoptosis as early as 6 hours, with an effect that continued up to 48 hours'."

Preclinical • Mantle Cell Lymphoma

The CDK9 inhibitor enitociclib overcomes resistance to BTK inhibition and CAR-T therapy in mantle cell lymphoma. (PubMed, Biomark Res) - "Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CASP3 • CCND1 • MCL1 • MYC

Synergy of ZEN3694 and VIP152 for dual transcriptional targeting of BET and CDK9 in patient derived organoid models of pancreatic cancer (AACR 2024) - "Here, we show the activity of dual transcription targeting with BET and CDK9 inhibition in patient derived pancreatic cancer organoid models. The combination of ZEN3694 and VIP152 has in vitro synergy in PDAC PCO models with on target activity. Ongoing work is validating this combination in animal models to assess toxicity, in vivo activity, and RNA expression profiling to understand transcriptional pathway dependency and therapeutic resistance."

Clinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2L1 • CDK7 • CDK9 • KRAS • RBP1

CDK9 inhibitors modulate the transcriptional landscape of colorectal cancer to suppress MAPK signaling and synergizes with BRAF inhibitors to treat BRAF-mutant colorectal cancer (AACR 2024) - "Cyclin-dependent kinase 9 (CDK9) is a key activator of RNA Pol II transcription and promotes the expression of many cancer driver genes, making CDK9 a promising target for cancer therapy. Human CRC cell lines, patient-derived organoids (PDOs), cell line xenografts, and patient-derived xenografts were used to investigate the efficacy and mechanisms of action of the CDK9 inhibitors AZD4573, enitociclib, and NVP-2, as well as the BRAF inhibitors encorafenib and dabrafenib. We have found CDK9 inhibitors to potently suppress CRC growth and survival through a unique mechanism of action, by vertical suppression of the MAPK signaling pathway. We demonstrate that CDK9 inhibitors can synergize with BRAF inhibitors in the treatment of BRAF-mutant CRC models. Thus, CDK9 inhibitors are a promising class of drugs warranting further investigation, including early-phase clinical trials, in mCRC."

Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Solid Tumor • EGFR • KRAS • MYC

Application of high-grade serous ovarian cancer organoids in functional precision medicine (AACR 2024) - "In several patients, we observed a pronounced cytotoxicity of several cyclin-dependent kinase (CDK) inhibitors, all of which potently inhibit CDK9, including two selective inhibitors (AZD4573 and VIP152) in clinical development. A platform for efficient establishment and drug-response profiling of high-grade serous ovarian cancer organoids. Developmental Cell (2023)"

Hematological Malignancies • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2

Targeting CDK9 with a novel potent and selective inhibitor, YX0798, in CAR-T-relapsed mantle cell lymphoma models (AACR 2024) - "Targeting CDK9 with its inhibitors AZD4573 and enitociclib is safe and effective for treatment in preclinical MCL models, and they are currently under clinical investigation to assess their efficacy and safety. This treatment efficacy was found to be similar at that of AZD4573 but at a higher dosage (15+15 mg/kg, 2 hours split, QW, IP). No adverse effects in mice were observed for any of treatments.ConclusionThese data show that our novel CDK9 inhibitor YX0798 is potent and efficacious in treating aggressive MCL models and overcame CAR-T resistance at a lower dosage than AZD4573."

IO biomarker • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • CDK9 • MCL1 • MYC

Study of VIP152, Venetoclax, and Prednisone (VVIP) in Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Mar 2024 ➔ Mar 2025

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

Vincerx Pharma Announces Compelling Clinical Efficacy of Enitociclib in Combination with Venetoclax and Prednisone in Lymphoma (GlobeNewswire) - P1/2 | N=130 | NCT05371054 | "Vincerx Pharma...announced promising clinical results from a Phase 1 NIH-sponsored study of enitociclib in combination with venetoclax and prednisone for the treatment of relapsed/refractory lymphoma....'Outcomes for patients with PTCL are extremely poor, with median progression-free survival and overall survival of 3.1 and 5.5 months, respectively'....Investigators from the National Institutes of Health (NIH) report 2 partial responses (PR) in 3 peripheral T-cell lymphoma (PTCL) patients and 1 PR in 2 double-hit diffuse large b-cell lymphoma (DH-DLBCL) patients in ongoing dose-escalation trial of enitociclib in combination with venetoclax and prednisone. Vincerx remains on target to report early clinical data from lead VersAptx™ platform compounds, VIP236 (early 2024) and VIP943 (mid 2024)."

P1 data • Diffuse Large B Cell Lymphoma • Peripheral T-cell Lymphoma • Solid Tumor

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

VNC-152-102: A Study to Evaluate VIP152 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Richter Syndrome (clinicaltrials.gov) - P1 | N=6 | Terminated | Sponsor: Vincerx Pharma, Inc. | N=54 ➔ 6 | Trial completion date: Feb 2026 ➔ May 2023 | Recruiting ➔ Terminated | Trial primary completion date: Feb 2026 ➔ May 2023; Slow enrollment

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • MYC

Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription. (PubMed, Cancer Res Commun) - "An unbiased analysis of the genes affected by CDK9 inhibition in both cell lines demonstrates that RNA polymerase II and transcription pathways are primarily affected and novel enitociclib targets such as PHF23 and TP53RK are discovered. These findings are recapitulated in blood samples from enitociclib-treated patients; while MYC downregulation is most robust with enitociclib treatment, other CDK9 regulated targets may be MYC independent delivering a transcriptional downregulation via RNA polymerase II."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • MCL1 • MYC