SNS-032 / Viracta Therap - LARVOL DELTA

Pan-CDK and PLK1 inhibitors as a novel approach for targeted treatment of adrenocortical carcinomas. (PubMed, Eur J Endocrinol) - "This study investigated the anti-tumour efficacy of the pan-CDK inhibitors (CDKi) dinaciclib, AT7519, and SNS-032; the CDK1-cyclin B1 inhibitor cucurbitacin E (curE); the PLK1 inhibitors (PLK1i) poloxin and plogosertib; and selected combination strategies in four genetically heterogeneous ACC cell lines (NCI-H295R, JIL-2266, MUC-1, TVBF-7) and primary cultures. These results identify dinaciclib and plogosertib as the most effective inhibitors across all ACC models tested. Their simultaneous action on multiple checkpoints, alongside with their synergistic effect in selected cell lines, suggest a potential benefit of their use in ACC that needs to be further investigated in vivo."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CCNB1 • CCNE1 • CDK1 • CDKN1A • CYP17A1 • CYP1A2 • CYP21A2 • MUC1

DISCOVERY OF CDK9/EZH2 INHIBITORS TO ENHANCE ANTI-PROLIFERATIVE ACTIVITIES FOR THE TREATMENT OF DLBCL (EHA 2026) - "Then, we previously synthesized a series of dual inhibitors targeting CDK9 and EZH2 by linking CDK9 inhibitors (KI-ARV-03/SNS-032) and EZH2 inhibitor (C24), and found compound D16 exhibited potent anti-proliferative activities in DLBCL and various solid tumor cells...Results We initially employed linkers of varying chain lengths to connect the self-discovered CDK9 inhibitor Hu754 and EPZ6438 pharmacophores based on D16 D16...(B) Quantitative evaluation of apoptosis in U-2932 cells after 48 hours of A9 pretreatment. (C) Levels of apoptosis-related proteins in U-2932 cells following 48 hours of A9 pretreatment."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor • ANXA5 • CDK9 • H2AX • MYC • RAD51

COMPUTATIONAL IDENTIFICATION OF A MONOCYTIC-METABOLIC VENETOCLAX-RESISTANT AML SUBTYPE WITH CDK INHIBITOR VULNERABILITY (EHA 2026) - "Dose-response matrices demonstrated significant synergy between VEN and CDK7/9 inhibitor SNS-032 in MM-AML like cells. VEN+CDK inhibitor combinations demonstrate promising activity in relapsed/refractory MM-AML patient samples with acceptable selectivity for normal hematopoietic cells. These findings establish a precision medicine framework for overcoming VEN resistance in monocytic AML and warrant further clinical investigation of VEN+CDK inhibitor combinations in biomarker-selected patients."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Inflammatory Arthritis • Leukemia • ANXA5 • CD34 • CDK2 • CDK7 • CDK9 • DNMT3A • IDH1 • IDH2

Drug screening of sarcoma cells: finding shared sensitivities. (PubMed, Cancer Res Commun) - "Interestingly, SNS-032 abrogates the downstream YAP pathway, a known driver pathway in the growth of these histotypes. Therefore, similar drug responses across histologies may indicate shared driver pathways and vulnerabilities."

Journal • Ewing Sarcoma • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma

Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway. (PubMed, Transl Oncol) - "We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • BCL2 • CASP3 • CD8 • IL1B • IL6 • NNMT • TGFB1 • TNFA

RBX1 loss sensitizes tubo-ovarian, high-grade serous ovarian cells to CDK2 inhibition by SNS-032. (PubMed, Front Cell Dev Biol) - "To our knowledge, this is the first demonstration of a SL interaction that exploits a heterozygous disease state in HGSC. These findings highlight CDK2 inhibition as a promising precision medicine strategy for RBX1-deficient tumors, broaden the applicability of SL approaches beyond homozygous gene loss, and provide strong preclinical rationale for further therapeutic development."

Journal • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • CASP3

Discovery of a First-in-Class Murine Double Minute 2-Recruiting Positive Transcription Elongation Factor B PROTAC Degrader With Selective Antitumor Activity. (PubMed, MedComm (2020)) - "To overcome this limitation, we designed a series of highly efficient and selective P-TEFb degraders by conjugating the CDK9 inhibitor SNS032 with the mouse double minute 2 (MDM2) ligand RG7388. Collectively, this study establishes dCDK9-010 as a first-in-class, selective MDM2-recruiting P-TEFb degrader. By enabling the elimination of the entire P-TEFb complex, this MDM2-recruiting degradation strategy expands the toolkit for targeting CDK9 and represents a promising new therapeutic paradigm for TP53 wild-type cancers."

Journal • Preclinical • Ewing Sarcoma • Lung Cancer • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation

Neuronal cells derived from iPSCs cell to evaluate neurotoxicity after 48 or 72 hours in high-through put screening format (AACR 2024) - "Bortezomib (proteasome inhibitor), gemcitabine (approved ovarian cancer treatment), ivermectin (parasitic diseases treatment), flavopiridol (approved CDKs inhibitors), SNS-032 (approved CDKs inhibitor), mefloquine (anti-malaria drug), digitonin (nonionic detergent) and tamoxifen (hormone receptor-positive breast cancer treatment). In conclusion, this panel is a good tool to anticipate possible neurotoxicity within the 3Rs respect. It can be used in early drug de-risking or neuroprotection screening, with the aim of preventing/reducing/curing neuropathy in at-risk populations."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

Rewiring cancer drivers to induce apoptosis in chronic lymphocytic leukemia (AACR 2025) - "TCIP2 is designed and produced by covalently linking BI-3812 (BCL6 inhibitor) as a BCL6 binder and SNS-032 (CDK9 inhibitor) as a CDK9 binder with a rigid linker. This is the first study of TCIPs ability to target CLL B cells from both untreated and RR patients. Further studies to more fully evaluate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the potential role of TCIPs as a novel therapeutic approach in CLL."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL6 • BRD4

An epigenetic bifunctional that toggles between transactivation and repression. (PubMed, bioRxiv) - "We tested these bifunctionals in a FKBP(F36V)-tagged transcription factor reporter system and found bifunctional induced transactivation is relatively common, being observed for bifunctionals with BET ligand JQ1, p300/CBP ligand GNE-781, CDK9 ligand SNS-032, and BRD9 ligand iBRD9. Together, these data establish bifunctionals targeting p300/CBP that toggle between a program of ultra-potent transactivation and repression depending on cellular context. Overall demonstrating that induced proximity with a given ligand does not encode a fixed functional outcome."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • CDK9

Elucidating Transcriptional Heterogeneity in Venetoclax Resistant AMLs (ASH 2024) - "These tumors also show higher sensitivity to CDK inhibitor SNS-032 (SNS), in part through suppression of OXPHOS and MTORC1 signaling...VR_C3-like cell-lines are sensitive to the JAK inhibitor ruxolitinib (RUXO)...Conclusion : We identified and characterize transcriptionally distinct subset/states of VEN resistant AMLs that can facilitate interrogation of inter and intra tumor heterogeneity associated with VEN resistance. The granularity captured by these states can guide development of new therapeutic approaches and their effective application in the clinical setting."

Heterogeneity • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Inflammatory Arthritis • Leukemia • Oncology • ASXL1 • BCL2 • DNMT3A • IDH1 • KRAS • NRAS • SRSF2 • TP53

Rewiring Cancer Drivers to Induce Apoptosis By Transcriptional Chemical Inducers of Proximity in Chronic Lymphocytic Leukemia (ASH 2024) - "CDK9-BCL6 TCIPs are designed and produced by covalently linking BI-3812 (binding to BCL6) and SNS-032 (binding to CDK9) with a rigid linker. This study is the first of a kind demonstration of TCIPs in robustly targeting CLL B cells. Further studies to fully validate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the role of TCIPs as a novel therapeutic approach in CLL."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2 • BCL6 • BRD4 • BTK • CD5 • CDK9 • TP53

Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects (EACR 2025) - "Notably, compound D16 induced greater DNA damage and exhibited stronger inhibitory effects on DLBCL proliferation compared to the single-target inhibitor SNS-032 or C24. All these findings highlight the potential of dual CDK9/EZH2 inhibitors as a novel approach for cancer therapy."

Diffuse Large B Cell Lymphoma • Oncology • Solid Tumor • CDK9

Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects. (PubMed, Eur J Med Chem) - "Notably, compound D16 induced more significant DNA damage and exhibited greater inhibition of DLBCL proliferation than the single-target inhibitor SNS-032 or C24. In addition, D16 showed potent anti-proliferative activities in various solid tumor cell lines, which may provide an innovative strategy for the treatment of cancer."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CDK9

Anticancer potential of novel benzothiazolyl piperidine-3-carboxamide derivatives as CDKs and VEGFR2 multi-target kinase inhibitors. (PubMed, J Comput Aided Mol Des) - "In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds 3 (IC50 0.026 µM) and 4c (IC50 0.048 µM) as compared to SNS-032 (IC50 0.052 µM) against CDK2, compounds 3 (IC50 0.315 µM), 4a (IC50 0.248 µM), 4b (IC50 0.276 µM), and 4c (IC50 0.338 µM) as compared to SNS-032 (IC50 0.476 µM) against CDK5, compounds 3 (IC50 0.221 µM), 4a (IC50 0.256 µM), 4b (IC50 0.282 µM), 4c (IC50 0.236 µM), and 4e (IC50 0.274 µM) as compared to SNS-032 (IC50 0.365 µM) against CDK6, and comparable potency of compound 4b (IC50 0.136 µM) with Sorafenib (IC50 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (3 and 4a-f) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity."

Journal • Oncology • CDK2 • CDK6 • KDR

SNS‑032 combined with decitabine induces caspase‑3/gasdermin E‑dependent pyroptosis in breast cancer cells. (PubMed, Oncol Lett) - "SNS-032 is a synthetic compound that specifically inhibits cyclin-dependent kinases 2, 7 and 9. In conclusion, these results suggest that caspase-3/GSDME-induced pyroptosis can be facilitated by SNS-032 treatment in BC cells, and DAC has the potential to enhance SNS-032-induced pyroptosis by increasing GSDME expression. This mechanistic insight indicates that SNS-032 is a promising therapeutic agent for BC treatment."

IO biomarker • Journal • B Cell Lymphoma • Breast Cancer • Lymphoma • Oncology • Solid Tumor • BCL2 • CASP3 • GSDME

Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations. (PubMed, Eur J Med Chem) - "By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1...Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins."

Journal • Targeted Protein Degradation • CDK2

Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases. (PubMed, ACS Med Chem Lett) - "Here, we first discovered the promiscuous kinase inhibitor SNS-032 and its derivative THAL-SNS-032 as binders of hCAR, then developed BODIPY FL SNS 032 (14) as a high-affinity hCAR fluorescent probe (K d: 300 ± 30 nM) in a TR-FRET binding assay and used it to characterize hCAR ligands for their competitive binding activities. BODIPY FL SNS 032 also displayed high binding affinities to multiple kinases, such as hGSK3A (K d: 4.5 ± 0.2 nM), hCDK9/CycT1 (K d: 5.1 ± 0.6 nM), hMAPK15 (K d: 340 ± 20 nM), hCASK (K d: 550 ± 30 nM), and hCAMKK2 (K d: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases."

Journal • MAPK15

Anti-EGFR antibody-drug conjugate carrying an inhibitor targeting CDK restricts triple-negative breast cancer growth. (PubMed, Clin Cancer Res) - "Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

CDK7 and CDK9 inhibition interferes with transcription, translation and stemness, and induces cytotoxicity in GBM irrespective of temozolomide sensitivity. (PubMed, Neuro Oncol) - "Our results suggest that CDK7 and CDK9 targeted-therapies may be effective against TMZ-sensitive and resistant GBM."

Journal • Alzheimer's Disease • Brain Cancer • CNS Tumor • Cognitive Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor • CDK7 • RPS6KB1 • SOX2 • SOX9

Discovery of HyT-based Degraders of CDK9-Cyclin T1 Complex. (PubMed, Chem Biodivers) - "In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader...Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • CDK9

Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia (AACR 2023) - "In summary, our study identified a highly synergistic drug combination, venetoclax and dinaciclib, for the treatment of hypodiploid B ALL, an aggressive leukemia with few effective current therapies. Finally, the promising results presented in this study may prompt further studies to support the inclusion of hypodiploid and other B-ALL patients to clinical trials combining phase I/II drugs against BCL-2 (mainly venetoclax) and CDK9 (dinaciclib, alvocidib, flavopiridol, SNS-032) or MCL-1 (MIK-665)."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CDK9 • MCL1

In silico enhancer mining reveals SNS-032 and EHMT2 inhibitors as therapeutic candidates in high-grade serous ovarian cancer. (PubMed, Br J Cancer) - "Here, we report the first attempt to exploit ovarian cancer epigenomic landscapes for drug discovery. This computational pipeline holds enormous potential for translating epigenomic profiling into therapeutic leads."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Piperlongumine conjugates induce targeted protein degradation. (PubMed, Cell Chem Biol) - "In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. Mechanistically, we identified KEAP1 as the E3 ligase recruited by 955 to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation."

Journal • Oncology • Targeted Protein Degradation • ALK • EML4 • KEAP1

Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction. (PubMed, Oncogene) - "We found that less-selective CDKIs, including flavopiridol, roscovitine, dinaciclib, and SNS-032, induced DR5 via p73-mediated transcriptional activation...CDKIs strongly synergized with 5-fluorouracil (5-FU), the most commonly used CRC chemotherapy agent, in vitro and in vivo to promote growth suppression and apoptosis, which required DR5 and p73. Together, these findings indicate p73-mediated DR5 induction as a potential tumor suppressive mechanism and a critical target engaged by different CDKIs in potentiating therapy-induced apoptosis in CRC cells. These findings help better understand the anticancer mechanisms of CDKIs and may help facilitate their clinical development and applications in CRC."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDK1 • TNFRSF10B