- |||||||||| BI-3812 / Boehringer Ingelheim, SNS-032 / Viracta Therap
Rewiring cancer drivers to induce apoptosis in chronic lymphocytic leukemia (Section 21; Poster Board No: 11) - Mar 25, 2025 - Abstract #AACR2025AACR_8106;
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.
- |||||||||| decitabine / Generic mfg., SNS-032 / Viracta Therap
Journal, IO biomarker: SNS?032 combined with decitabine induces caspase?3/gasdermin E?dependent pyroptosis in breast cancer cells. (Pubmed Central) - Mar 12, 2025
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.
- |||||||||| SNS-032 / Viracta Therap
Journal: Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations. (Pubmed Central) - Feb 22, 2025
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.
- |||||||||| SNS-032 / Viracta Therap
Journal: Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases. (Pubmed Central) - Nov 20, 2024
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. 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
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Elucidating Transcriptional Heterogeneity in Venetoclax Resistant AMLs (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5270;
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.
- |||||||||| Journal: Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction. (Pubmed Central) - Mar 21, 2023
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, dinaciclib (MK-7965) / Ligand, Merck (MSD)
Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia (Section 38; Poster Board #15) - Mar 14, 2023 - Abstract #AACR2023AACR_7079;
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).
- |||||||||| Zykadia (ceritinib) / Novartis, SNS-032 / Viracta Therap
Journal: Piperlongumine conjugates induce targeted protein degradation. (Pubmed Central) - Feb 27, 2023
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.
- |||||||||| SNS-032 / Viracta Therap
Journal: High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma. (Pubmed Central) - Nov 16, 2022
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.
- |||||||||| SNS-032 / Viracta Therap
Journal, PARP Biomarker, IO biomarker: SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9. (Pubmed Central) - Nov 1, 2022
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.
- |||||||||| Bavencio (avelumab) / EMD Serono, Pfizer, SNS-032 / Viracta Therap
Preclinical, Journal, PD(L)-1 Biomarker, IO biomarker: CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models. (Pubmed Central) - Jul 29, 2022
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.
- |||||||||| SNS-032 / Viracta Therap
Journal: Cyclin-dependent kinase 7/9 inhibitor SNS-032 induces apoptosis in diffuse large B-cell lymphoma cells. (Pubmed Central) - Apr 22, 2022
Mechanistically, SNS-032 inhibited RNA polymerase II, which led to transcriptional-dependent suppression of NF-κB signaling pathway and its downstream targets involved in cell survival; SNS-032 also downregulates BCL-2 and c-MYC in both mRNA and protein levels. Significantly, these findings provide pre-clinical evidence for application of targeting the CDK7/9 in DLBCL.
- |||||||||| SNS-032 / Viracta Therap
Journal: A SIX1 degradation inducer blocks excessive proliferation of prostate cancer. (Pubmed Central) - Apr 20, 2022
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.
- |||||||||| methotrexate / Generic mfg., sirolimus / Generic mfg.
Journal: Precipitate-Supported Thermal Proteome Profiling Coupled with Deep Learning for Comprehensive Screening of Drug Target Proteins. (Pubmed Central) - Feb 19, 2022
Using a promiscuous kinase inhibitor, staurosporine, we delineated 99 kinase targets with a specificity up to 83% in K562 cell lysates, which represented a significant improvement over the existing thermal shift methods. Furthermore, the PSTPP strategy was successfully applied to analyze the binding targets of rapamycin, identifying the well-known targets, FKBP1A, as well as revealing a few other potential targets.
- |||||||||| SNS-032 / Viracta Therap
Development of CDK16 chemical probes based on the SNS-032 scaffold (In-Person Room (Virtual Room)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_13166;
Guided by the available X-ray cocrystal structures of CDK2 and CDK16 inhibitors, we targeted replacement of the oxazole and the piperidine rings of SNS-032 with other building blocks to determine their in-cell target engagement selectivity by NanoBRET assay. Here we describe the structure activity relationships of a series of 5-substituted-2-carboxamide thiazole analogs at CDK16 and CDK2 and progress towards optimization of a cell active chemical probe.Figure 1: SNS-032 structure and proposed modification sites to improve CDK16 activity.
- |||||||||| SNS-032 / Viracta Therap
Journal: The molecular context of vulnerability for CDK9 suppression in triple wild-type melanoma. (Pubmed Central) - Nov 25, 2021
A drug screen identified a CDK9 inhibitor (SNS-032) to have therapeutic selectivity against wild-type (wt) BRAF/NRAS melanomas compared with BRAF/NRAS mutated melanomas...Human TCGA melanoma tumor data further supported a potential oncogenic role for E2F1/E2F2 in BRAF/NRAS/NF1 tumors and a direct link to CDK9. Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing therapeutically-orphaned BRAF/NRAS/NF1 wild-type melanomas.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, SNS-032 / Viracta Therap
[VIRTUAL] Delineating CDK9- regulated molecular events for the development of rationally derived multiple myeloma treatment strategies () - Aug 28, 2021 - Abstract #IMW2021IMW_332;
Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers. In summary, by delineating CDK9- regulated molecular events in MM, our studies strongly support the therapeutic role of targeted CDK9-therapy and rationally derived MM combination treatment strategies.
- |||||||||| Journal: CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. (Pubmed Central) - Apr 21, 2021
Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4.
- |||||||||| SNS-032 / Sunesis
Journal: A perspective on the discovery of selected compounds with anthelmintic activity against the barber's pole worm-Where to from here? (Pubmed Central) - Jul 22, 2020
Following the screening of 15,333 chemicals from five distinct compound collections against H. contortus, we have discovered one new chemical entity (designated SN00797439), two human kinase inhibitors (SNS-032 and AG-1295), 14 tetrahydroquinoxaline analogues, one insecticide (tolfenpyrad) and two tolfenpyrad (pyrazole-5-carboxamide) derivatives (a-15 and a-17) with anthelmintic activity in vitro...In our opinion, some of these compounds could represent starting points for 'lead' development. Accordingly, the next research steps to be pursued include: (i) chemical optimisation of representative chemicals via structure-activity relationship (SAR) evaluations; (ii) assessment of the breadth of spectrum of anthelmintic activity on a range of other parasitic nematodes, such as strongyloids, ascaridoids, enoplids and filarioids; (iii) detailed investigations of the absorption, distribution, metabolism, excretion and toxicity (ADMET) of optimised chemicals with broad nematocidal or nematostatic activity; and (iv) establishment of the modes of action of lead candidates.
- |||||||||| SNS-032 / Sunesis
[VIRTUAL] The molecular context of vulnerability for CDK9 suppression in melanoma () - Jul 1, 2020 - Abstract #SID2020SID_106;
In unpublished studies, we recently found that a cyclin-dependent kinase 9 (CDK9) degrader (Thal-SNS-032, TS-032) selectively inhibited BRAF/NRAS wild type melanomas...Overall, our results suggest that genes involved in the cell cycle lead to the unique vulnerabilities in triple wild-type and uveal cell lines against CDK9 inhibition. We may have further identified a unique “Achilles cluster” of genes anchored with the E2F pathway in triple wild-type and uveal melanomas.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California, Verzenio (abemaciclib) / Eli Lilly, SNS-032 / Sunesis Pharma
Journal: Proteome and Phosphoproteome Changes Associated with Prognosis in Acute Myeloid Leukemia. (Pubmed Central) - Mar 21, 2020
This suggests that therapy against the upregulated kinases could also target the factors inducing their upregulation rather than their activity. This study, therefore, presents markers that could help predict AML relapse and direct therapeutic strategies.
- |||||||||| Thalomid (thalidomide) / Fujimoto, BMS, SNS-032 / Sunesis
Functional Characterization of E3 Ligases and Their Regulators: Therapeutic Implications for Development of New Proteolysis-Targeting Chimeric Degraders of Oncoproteins (Hall E2, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_1706;
The discovery that thalidomide derivatives recruit the E3 ligase CRBN to induce neomorphic degradation of proteins critical for multiple myeloma (MM) cells stimulated the research into proteolysis-targeting chimeric compounds (PROTACs), led to development of several CRBN- or VHL-based PROTACs against various oncoproteins and put a new spotlight on the biology and therapeutic targeting of E3 ligases in human neoplasias...We thus performed genome-scale CRISPR-based gene editing (for loss-of-function, LOF) studies in MM.1S cells treated with PROTACs targeting BET bromodomain proteins through MDM2 (A1874), CRBN (dBET6) or VHL (ARV-771 or MZ-1) or targeting CDK9 through CRBN (Thal-SNS-032); and validated key hits with individual sgRNAs in different MM cell lines...KCMF1, RNF4) which, to our knowledge, have not been leveraged for design of PROTACs, but warrant consideration given their patterns of essentiality in “high expressor” tumor cells . Our study provides insights on differential regulation and distinct patterns of essentiality for different E3 ligases and informs the design of new PROTACs which leverage different E3 ligases to help delay/overcome treatment resistance in MM and beyond.
- |||||||||| doxorubicin hydrochloride / generics
Journal, IO Biomarker: Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma. (Pubmed Central) - Oct 27, 2019
In the combination screen, including BET, BTK and PI3K inhibitors, we identified synergistic combinations of PI3K and BTK inhibition with drugs targeting Akt, mTOR, BET and doxorubicin...The strongest synergy was observed for the combination of the CDK 2/7/9 inhibitor SNS032 and OTX015. Our data provide a landscape of drug combination effects in BL and suggest that targeting CDK and BET could provide a novel vulnerability of BL.
- |||||||||| Ibrance (palbociclib) / Pfizer, Verzenio (abemaciclib) / Eli Lilly
Differential mechanisms of acquired resistance to Abemaciclib versus Palbociclib reveal novel therapeutic strategies for CDK4/6 therapy-resistant breast cancers (Stars at Night Ballroom 1&2 - 3rd Level) - Sep 25, 2019 - Abstract #SABCS2019SABCS_1210;
Western blot analysis revealed a dose dependent downregulation of ERα, Rb, p-Rb and p27, while levels of cyclin E and p-CDK2 increased in a stepwise fashion in palbociclib resistant cells, which were only partially cross resistant to abemaciclib and sensitive to CDK9 inhibitors LDC067 and SNS032... Our results suggest that mechanisms underlaying palbociclib and abemaciclib acquired resistance exhibit differentially altered pathways, such as DNA damage/repair pathways, which can be exploited to overcome CDK4/6 inhibitors therapy resistance in breast cancer patients.
- |||||||||| Thalomid (thalidomide) / Celgene, Fujimoto Pharma, SNS-032 / Sunesis
Journal: Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. (Pubmed Central) - May 7, 2019
Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
- |||||||||| SNS-032 / Sunesis
Journal: Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. (Pubmed Central) - Feb 11, 2019
Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis...In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.Leukemia accepted article preview online, 14 August 2017. doi:10.1038/leu.2017.252.
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