THAL-SNS-032 / Dana-Farber Cancer Institute - LARVOL DELTA

Liposomal formulation of the CDK9 PROTAC THAL-SNS-032 enhances the antitumor activity in breast cancer cell lines. (PubMed, Biomed Pharmacother) - "Overall, incorporating THAL-SNS-032 into nanomedicines offers a comprehensive approach with potential benefits in dose optimization, safety, and targeted delivery. These findings support the further development of nanomedicine-based PROTAC therapies for cancer treatment."

Journal • Preclinical • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • CDK9

Cyclin-dependent kinase signaling in oncology: assessing the effectiveness of a CDK9-targeting using no-wash immunoassays (AACR 2025) - "Assessing CDK9 levels allowed the identification of a PROTAC degradation of CDK9 while the determination of GADPH levels was used as an internal control for potential changes to global protein levels in drug treatment.Cells were treated for 4h either with 1µM of a reference CDK9 degrader, Thal-SNS-032 or with the same concentration of its two individual chemical components, Thalidomide and SNS-032 (as negative controls). These data suggest that HTRF and ALSU assays are efficient solutions to identify and characterize PROTAC targeting of CDK9. Results obtained for CDK9 can be translated to other CDK targets of interest in oncology research as a broad portfolio of total CDK detection kits is available using the two assay platforms."

Oncology • CDK9 • GAPDH • MCL1 • XIAP

CETSA-based evaluation of non-degraded PROTAC targets (AACR 2025) - "Here we will exemplify how CETSA can be applied in deconvoluting protein binding of a CDK9 targeting PROTAC: THAL SNS 032, which is composed of the cereblon (E3-ligase) binder Thalidomide and the CDK (POI) binder SNS 032. The effects on the GSK3 - FOXK1 signaling axis would have been missed if only protein degradation had been considered. By combining mass spectrometric data from CETSA experiments with degradation readouts it is possible to correlate cellular target engagement potencies with degradation efficiency and importantly, also identify any drug - protein binding that do not result in degradation"

Oncology • CDK9 • CRBN • GSK3B

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

CDK9-dependent transcriptional regulation of BCMA in multiple myeloma: rational combination therapies (DGHO 2024) - " Having correlated CDK9 and BCMA expression in MM cells alone or in 2D- and 3D- coculture systems, the dependency of BCMA expression on CDK9 was demonstrated by genomic (transient siCDK9- and inducible Tet-on/shCDK-9-) approaches or by the proteolysis targeting chimera Thal-SNS-032 through selective degradation of CDK9. In summary, although therapeutic inhibition of CDK9 is a promising evolving option in MM therapy, its impact on strategies involving BCMA- targeting agents warrant further consideration for clinical application."

Combination therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CDK9

Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs. (PubMed, J Med Chem) - "Herein, systematic optimization of coumarin analogs linked with the CDK9 inhibitor SNS-032 is reported that may bind to cyclin-dependent kinase 9 (CDK9) and microtubule-associated protein 1 light chain 3 beta (LC3B) simultaneously, which leads to the selective autophagic degradation of targeted CDK9/cyclin T1 and is different from the PROTAC degrader THAL-SNS-032...In addition, degrader 10 showed antitumor efficacy in vivo. Our work optimized a potent LC3B recruiter and demonstrated the feasibility of autophagy-tethering compounds (ATTECs), which could be applied for the degradation of diverse intracellular pathogenic proteins to treat related diseases."

Journal • Oncology • Targeted Protein Degradation • CDK9

Delineating CDK9- Regulated Molecular Events for the Development of Rationally Derived Multiple Myeloma Treatment Strategies (ASH 2022) - "Moreover, knockdown CDK9 by shRNA inhibited proliferation and survival, both in MM tumor cell- and tumor cell/BMSC co-cultures. Rationally derived combination strategies of Thal-sns-032 with venetoclax, navitoclax, Selinexor or Carfilzomib as well as other investigational and established MM therapies induced synergistic anti-MM effects in MM cells or BMSC co-cultures.Conclusion : 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."

IO biomarker • Hematological Disorders • Hematological Malignancies • Inflammatory Arthritis • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Targeted Protein Degradation • BCL2 • CDK2 • CDK7 • CDK9 • MCL1 • MYC • TP53

Cdk-9 Degrader THAL-SNS-032 Enhances the Anti-tumor Effects of EZH2 Inhibitor DZNep in Pancreatic Ductal Adenocarcinoma (PDAC) (ACS-CLINCON 2022) - "CDK-9 inhibition enhances the anti-proliferative and pro-apoptotic effects of EZH2 inhibition in PDAC cells and warrants further clinical investigation. >"

IO biomarker • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2 • CDK9 • CDKN1A

Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer. (PubMed, J Med Chem) - "LL-K9-3 exhibited enhanced anti-proliferative and pro-apoptotic effects compared with its parental CDK9 inhibitor SNS032 and suppressed downstream signaling of CDK9 and AR more effectively than SNS032. Moreover, LL-K9-3 inhibited AR and Myc-driven oncogenic transcriptional programs and exerted stronger inhibitory effects on several intrinsic target genes of AR than the monomeric CDK9 PROTAC (Thal-SNS032)."

Journal • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Psychiatry • Solid Tumor • Targeted Protein Degradation • AR • CDK9 • MYC