- |||||||||| THAL-SNS-032 - Dana / Farber Cancer Institute
CETSA-based evaluation of non-degraded PROTAC targets (Section 18; Poster Board No: 27) - Mar 25, 2025 - Abstract #AACR2025AACR_3188;
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
- |||||||||| ASXL1 mutations in AML are associated with a distinct epigenetic state that results in vulnerabilities to epigenetic-targeted agents (Section 20; Poster Board No: 5) - Mar 25, 2025 - Abstract #AACR2025AACR_3142;
Our findings confirm the previously published discovery that the presence of mtASXL1 confers an increased sensitivity to BETi inhibitors, e.g., pelabresib or birabresib...Importantly, in the NSG mice engrafted with OCIAML3 ASXL1 Y591*, monotherapy with NEO2734, pelabresib or SEL120 significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or mediator-kinase inhibitor.
- |||||||||| A novel class of multitarget small molecule PI3K-CDK4/6-CDK9-AURAKA/B inhibitor harnesses Warburg effect against non-small cell lung cancer (Section 17; Poster Board No: 13) - Mar 25, 2025 - Abstract #AACR2025AACR_3088;
LCI139-sensitive (NCI-H1703) and resistant (NCI-H1781) human NSCLC cells, identified from prior IC50 experiments, were treated with LCI139 (0.25 and 0.5?M) or single agent inhibitors PI3Ki (BKM120), CDK4/6i (Ribociclib), CDK9i (AZD4573), and AURKAi (Alisertib). Multitarget inhibitor, LCI139 is uniquely designed to harness the Warburg effect to induce synthetic lethality in glycolysis-reliant NSCLC by 1) inducing metabolic stress (pAMPK), 2) lowering the threshold to metabolic stress response (FoxO3 stabilization), and 3) enhancing caspase-dependent cell death non-canonical Cas8 activation.
- |||||||||| enitociclib (VIP152) / Vincerx, zemirciclib (AZD4573) / AstraZeneca
Drug discovery of potent and specific CDK9 protein degraders for the treatment of refractory lymphomas (Room S402 - McCormick Place South (Level 4)) - Mar 25, 2025 - Abstract #AACR2025AACR_2361;
Several promising potent and specific CDK9 degraders such as YX0597 have been identified. YX0597 is a bona fide CDK9 degrader highly effective against various resistant MCL cells, induces cell apoptosis and suppresses the tumor growth in vivo at a very low dosage in a PDX mouse model with dual resistance to BTKi and CAR-T, indicating its potential for the treatment of refractory lymphomas including resistant MCL.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2. (Pubmed Central) - Mar 1, 2025
Notably, we demonstrate that low CDK9 and high HDAC2-AS2 expressions are associated with poor survival of HCC, which can be rescued by anti-PD-1 therapy. These findings emphasize the significance of tumor-derived EVs in suppressing antitumor CD8+ T cell immunity to promote tumorigenesis, and highlight extracellular HDAC2-AS2 as a promising biomarker and therapeutic target for HCC.
- |||||||||| alvocidib (DSP-2033) / Sumitomo Pharma
Therapeutic Potential of Flavopiridol in the Suppression of Lung Fibrosis Via CDK9 Inhibition (Area L, Hall F (North Building, Exhibition Level), Moscone Center; Poster Board # P1470) - Feb 24, 2025 - Abstract #ATS2025ATS_3742;
Our findings suggest that CDK9 serves as a critical regulator of fibrogenesis in IPF and that inhibiting CDK9 through the use of flavopiridol represents a promising therapeutic strategy. The formulation of a novel method for the pulmonary delivery of flavopiridol presents a potential targeted treatment approach for IPF.
- |||||||||| 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.
- |||||||||| AT7519 / Novartis, Otsuka
Journal: Identification of a Potent and Selective CDK9 Degrader as a Targeted Therapeutic Option for the Treatment of Small-Cell Lung Cancer. (Pubmed Central) - Feb 3, 2025
In this study, a potent and selective CDK9 degrader, C3, was developed through PROTAC modification of the CDK9 inhibitor, AT-7519...Our findings indicate that the targeted degradation of CDK9 could become a viable strategy for treating SCLC, highlighting its potential therapeutic value. Additionally, this research offers a general structural optimization and evaluation strategy to improve the degradative selectivity, metabolic stability, and oral availability of PROTAC molecules.
- |||||||||| fadraciclib (CYC065) / Cyclacel
Journal: Design, Synthesis and Biological Evaluation of Novel 9H Purine Derivatives as Potent CDK9 Inhibitors. (Pubmed Central) - Jan 31, 2025
Taking the CDK2/9 inhibitor CYC065 as the positive control and an in-house library compound (64) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure-activity relationships (SAR)...After conducting selectivity testing against CDK2/9 kinase, compound B5 demonstrated approximately five-fold greater selectivity towards CDK9-cyclinT1 over CDK2-cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors.
- |||||||||| Preclinical, Journal: LDC000067, a CDK9 inhibitor, unveils promising results in suppressing influenza virus infections in vitro and in vivo. (Pubmed Central) - Jan 31, 2025
Mechanistically, we showed that LDC treatment and CDK9 silencing reduce Pol II expressions, a requisite host protein for viral RNA transcription. Altogether, our findings indicate that CDK9 could be a promising target for developing antivirals against influenza virus infections, and LDC, with its strong anti-influenza properties, instills confidence in its potential as an effective anti-influenza agent.
- |||||||||| NCB-0846 / Carna Biosci
Journal: Identification of a TNIK-CDK9 axis as a targetable strategy for platinum-resistant ovarian cancer. (Pubmed Central) - Jan 28, 2025
This identified TNIK, which is modulated by NCB-0846, as a novel target for platinum-resistant HGSC...Our findings identified the TNIK-CDK9 axis as druggable targets mediating platinum resistance and cell viability in HGSC. With AI at the forefront of drug discovery, this work highlights how to ensure that AI findings are biologically relevant by combining compound screens with physiologically relevant models thus supporting the identification and validation of potential drug targets.
- |||||||||| SLS009 / SELLAS Life Sciences
Preclinical, Journal: Preclinical metabolism and disposition of [14C]GFH009, a novel selective CDK9 inhibitor. (Pubmed Central) - Dec 18, 2024
Besides, the major clearance pathway for GFH009 was excretion and the minor one was metabolism.5. GFH009 exhibits favourable drug metabolism and pharmacokinetics (DMPK) properties, which provides valuable insights into the disposition of GFH009 and can be used to guide future clinical studies.
- |||||||||| Journal: Crosslink among cyclin-dependent kinase 9, ATP binding cassette transporter G2 and Beclin 1 in colorectal cancer. (Pubmed Central) - Dec 16, 2024
The incidence of autophagy and the expressions of Beclin 1 and ATP binding cassette transporter G2 are different in left and right colon cancer, and autophagy may be involved in the occurrence of chemotherapy resistance. In this article, the roles of CDK9, ATP binding cassette transporter G2 and Beclin 1 in CRC were elucidated, emphasizing the linkages among them and providing potential therapeutic targets of CRC.
- |||||||||| Review, Journal: Role of specific CDKs in regulating DNA damage repair responses and replication stress. (Pubmed Central) - Dec 9, 2024
In this review, we focus on the intricate ways by which specific CDKs mainly CDK7, CDK9, and CDK12/13, regulate the cell cycle progression and transcription and how their modulation can lead to lethal effects on the integrity of the genome. With a better knowledge of how these CDKs control the DDR and replication stress, it is now possible to combine CDK inhibitors with chemotherapeutic drugs that damage DNA in ways that can be applied in clinical settings as successful therapeutic strategies.
- |||||||||| enitociclib (VIP152) / Vincerx, zemirciclib (AZD4573) / AstraZeneca
Orally Effective CDK9 Inhibitor YX0798 for Treating Aggressive Lymphoma () - Dec 7, 2024 - Abstract #ASH2024ASH_9502;
Mechanistically, YX0798 or the commercial competitor led to CDK9 inhibition and primarily resulted in downregulation of short-lived oncoprotein c-MYC and pro-survival protein MCL-1. Ultimately, CDK9 inhibition disrupted the cell cycle and switched cellular metabolism towards oxidative phosphorylation, eventually leading to cell death.ConclusionsTogether, our study demonstrates that YX0798 is an orally bioavailable CDK9 inhibitor with exquisite selectivity and anti-tumor potency that drives transcription reprogramming towards tumor cell killing.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Dysregulation of Transcription Machinery Drives the Acquisition of BTK Inhibitor and Venetoclax Treatment Resistance in Mantle Cell Lymphoma () - Dec 7, 2024 - Abstract #ASH2024ASH_8285;
Taken together, this work demonstrates that the adaptive transcriptional machinery activation and immune-responsive TME state transition induced by BTKi-venetoclax are therapeutic vulnerabilities that may be effectively exploited by both targeted- (e.g., CDK9 inhibitors) and immune-therapies (e.g., CD19 CAR-T) to overcome MCL therapy resistance. This highly translational work has the potential to have an immediate impact on MCL treatment approaches through the rational design of new combination regimens.
- |||||||||| zemirciclib (AZD4573) / AstraZeneca
Combinatorial Therapy of CDK9 Inhibitor with CD19 CAR-T to Reciprocally Overcome Therapy Resistance and Enhance Treatment Efficacies Against Aggressive B-Cell Lymphomas () - Dec 7, 2024 - Abstract #ASH2024ASH_8284;
In doing so, we are able to demonstrate that : 1) DLBCL and MCL are exquisitely sensitive to CDK9 inhibition (NVP2/AZD4573) regardless of genetic background or resistance status, 2) populations of CDK9i (NVP2/AZD4573) treatment-induced drug tolerant persister (DTP) cells are responsible for driving therapy resistance evolution, 3) CDK9i (NVP2/AZD4573) treatment induces an immunogenic response via activation of proinflammatory and IFN pathways ex vivo and in vivo, and 4) CDK9i and CD19 CAR-T therapies exhibit reciprocally enhanced efficacy in a manner that can overcome therapy resistance in DLBCL and MCL. The outcomes of this study have broad applicability across B-cell malignancies for eradicating both targeted and CAR-T therapy resistance, which we anticipate can be readily translated to the clinic and have immediate impact on DLBCL/MCL patient care.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, dinaciclib (MK-7965) / Merck (MSD)
CDK9 Inhibition Sensitizes TP53 Mutated AML to Standard Chemotherapy () - Dec 7, 2024 - Abstract #ASH2024ASH_7880;
This action was less pronounced in normal PBMCs. We have ongoing experiments testing this drug combination on normal human CD34+ cells to better determine a therapeutic window to maximize apoptosis in leukemia cells while causing the least cytotoxicity in normal human cells, which should lead to validation studies in vivo.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
LARP1 Regulates Leukemogenesis of AML By Altering Cell Metabolism and mRNA Translation () - Dec 7, 2024 - Abstract #ASH2024ASH_7820;
The results reveal that loss of LARP1 as well as inhibition of mTOR and CDK9 by small molecule antagonists diminish levels of some important oncometabolites. Altogether our findings suggest that LARP1 could be a potential therapeutic target for AML and warrants future drug discovery efforts to create LARP1 targeting small molecules.
- |||||||||| zemirciclib (AZD4573) / AstraZeneca
Journal: Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition. (Pubmed Central) - Dec 6, 2024
We also conducted in vivo studies in a leukemic xenograft model, where AZD4573 treatment led to significant tumor regression, decreased ATAT1 expression, and ?-tubulin degradation. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts ?-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors.
- |||||||||| 5-fluorouracil / Generic mfg.
Journal: Heterocycle-functional steroidal derivatives: Design, synthesis, bioevaluation and SARs of steroidal pyrazolo[1,5-a]pyrimidines as potential ALK inhibitors. (Pubmed Central) - Dec 3, 2024
The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5-a]pyrimidine might be affected by the ?-hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63
- |||||||||| Journal: Synthesis and cytotoxic activity of some (+)-salsolidine derivatives. (Pubmed Central) - Nov 13, 2024
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 As a result of the screening, the hit compound - 2-(chloroacetyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (11) was identified, that inhibited the metabolic activity of A-549, MCF-7 and SH-SY5Y tumour cell lines with the IC values of 3.83?
- |||||||||| Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5196;
Relapsed disease has poor prognosis, especially after immunotherapeutic approaches have failed, including blinatumomab (bispecific T cell engager BITE) and chimeric antigen receptor T-cell (CAR-T) therapy...Methods : Venetoclax, alvocidib, S63845 (MCL1i), dexamethasone and tyrosine kinase inhibitors (TKIs) were from Selleckchem...Conclusions : Simultaneous inhibition of BCL-2 and CDK9 represents an effective approach for targeting Ph+, KMT2AR and CD19-/- B-ALL without need for additional DNA-damaging chemotherapy or kinase inhibition. Taken together, this provides strong rationale for the clinical translation of venetoclax combined with alvocidib in patients with poor prognosis ALL, thereby offering a promising novel combination treatment for CAYA.
|
