SNS-032 / Viracta Therap - LARVOL DELTA

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

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

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

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

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

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

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

Abemaciclib drug combination screening with other targeted therapies in complex multicellular tumor spheroids (AACR-NCI-EORTC 2022) - "The combination of abemaciclib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or synergistic cell killing in several of the cell lines screened. The KRAS G12C selective inhibitor sotorasib in combination with abemaciclib was active in the two KRAS G12C variant containing cell lines. The most effective combination for abemaciclib was with the CDK2/7/9 inhibitor BMS-387032, which achieved greater than one log of cytotoxicity in the majority of the complex spheroid models...HHSN261201500003I. No"

Oncology • KRAS

High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma. (PubMed, Pharmaceuticals (Basel)) - "With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies."

Journal • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9. (PubMed, Front Pharmacol) - "In active HSCs with CDK9 knockdown, the expression levels of CDK9, phosphorylated RNA polymerase II, XIAP, Bcl-2, Mcl-1, and ɑ-SMA significantly decreased, whereas those of cleaved-PARP1 and Bax decreased prominently. These results indicated that SNS-032 is a potential drug and CDK9 might be a new prospective target for the treatment of liver fibrosis."

IO biomarker • Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Oncology • BCL2 • CDK9 • MCL1 • XIAP

SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. (PubMed, Acta Pharmacol Sin) - "Moreover, we showed that sorafenib combined with SNS-032 or gefitinib synergistically inhibited the growth of Hep3B xenografts in vivo. Overall, we identify that both SIX1 and RPS16 are crucial substrates for the EGFR-AKT-USP1 axis-driven growth of HCC, suggesting a potential anti-HCC strategy from a novel perspective."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • USP1

CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models. (PubMed, Cancers (Basel)) - "In tumor-bearing mice engrafted with human immune cells, the anti-PD-L1 antibody avelumab, given sequentially following suboptimal SNS-032 dosing, reduced tumor growth compared with SNS-032 alone or with avelumab without prior SNS-032 priming. CDK inhibition at suboptimal doses promotes immune cell recruitment to tumors, PD-L1 expression by surviving TNBC cells and may complement immunotherapy."

IO biomarker • Journal • Preclinical • Breast Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • Triple Negative Breast Cancer • PTPRC

Large-scale in vitro and in vivo CRISPR-Cas9 knockout screens identify a 16-gene fitness score for improved risk assessment in acute myeloid leukemia. (PubMed, Clin Cancer Res) - "Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies."

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

Pharmacological targeting of TFIIH suppresses KRAS mutant pancreatic ductal adenocarcinoma and synergizes with TRAIL. (PubMed, Cancer Res) - "TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (Triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. All three drugs exhibited synergy in combination with a multivalent TNF-related apoptosis inducing ligand (TRAIL), effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy with direct translational implications for current clinical trials on metastatic pancreatic cancer patients."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CASP8 • CDK7 • CDK9 • KRAS • TP53 • XIAP

A New Approach to Drug Repurposing with Two-Stage Prediction, Machine Learning, and Unsupervised Clustering of Gene Expression. (PubMed, OMICS) - "Consequently, we found disease-specific gene expression, and importantly, identified 20 drugs such as BMS-387032, phorbol-12-myristate-13-acetate, mitoxantrone, alvocidib, and vorinostat as candidates for repurposing. That is, inclusion body myositis and DM. The two-stage prediction approach to drug repurposing presented here offers innovation to inform future drug discovery and clinical trials in a variety of human diseases."

Journal • Dermatomyositis • Immunology • Infectious Disease • Myositis • Novel Coronavirus Disease

Drug combination screening of Ipatasertib and Abemaciclib with other targeted agents in complex multicellular tumor spheroids from the NCI-60 and the National Cancer Institute’s Patient-Derived Models Repository (AACR 2022) - "For example, the combination of ipatasertib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or synergistic cytotoxicity in over half the complex spheroid models screened. The V600E variant-specific BRAF inhibitor vemurafenib and the KRAS G12C selective inhibitor sotorasib in combination with ipatasertib showed activity in the one BRAF V600E and two KRAS G12C variant containing complex spheroid models, respectively. Another effective ipatasertib combination was vertical inhibition of the PI3K/AKT/mTOR pathway with the mTORC1/2 kinase inhibitor sapanisertib, which demonstrated additive and/or synergistic responses across multiple complex spheroid models. For abemaciclib, the most successful combination was with the CDK2/7/9 inhibitor BMS-387032, which achieved greater than one log of cytotoxicity in the majority of the complex spheroid models...This project was funded in part with federal funds from the NCI, NIH, under contract..."

Clinical • Oncology • KRAS

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer. (PubMed, Int J Biol Sci) - "Moreover, the combination of SNS-032 and enzalutamide synergistically induces apoptosis and downregulates expression of USP1, SIX1, and AR/AR-V7 in AR-V7 highly expressed 22Rv1 cells. Overall, our findings may develop a novel and effective strategy to overcome castration resistance in PC for the identification of a SIX1 degradation inducer via targeting the USP1-SIX1 axis."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • HSPA9 • USP1