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    DRUG:

    THAL-SNS-032

    i
    Other names: THAL-SNS-032
    Company:
    Dana-Farber Cancer Institute
    Drug class:
    CDK9 degrader
    7ms
    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.
    Preclinical • Journal
    |
    CDK9 (Cyclin Dependent Kinase 9)
    |
    THAL-SNS-032
    3years
    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
    |
    TP53 (Tumor protein P53) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • CDK2 (Cyclin-dependent kinase 2) • CDK7 (Cyclin Dependent Kinase 7) • CDK9 (Cyclin Dependent Kinase 9)
    |
    Venclexta (venetoclax) • Xpovio (selinexor) • navitoclax (ABT 263) • carfilzomib • THAL-SNS-032
    over3years
    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
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • AR (Androgen receptor) • CDK9 (Cyclin Dependent Kinase 9)
    |
    AR expression
    |
    THAL-SNS-032
    over3years
    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
    |
    BCL2 (B-cell CLL/lymphoma 2) • CDK9 (Cyclin Dependent Kinase 9) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    THAL-SNS-032
    over3years
    Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer. (PubMed, Int J Mol Sci)
    BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • CDK9 (Cyclin Dependent Kinase 9)
    |
    HER-2 positive • ER positive • HER-2 overexpression
    |
    Herceptin (trastuzumab) • THAL-SNS-032