- |||||||||| OMO-103 / Peptomyc
Review, Journal, IO biomarker: Rethinking MYC inhibition: a multi-dimensional approach to overcome cancer's master regulator. (Pubmed Central) - May 14, 2025
However, recent advances are overturning this view, with direct inhibitors like Omomyc (OMO-103) and PROTAC-based degraders such as WBC100 showing promising clinical progress...Moreover, combination therapies integrating MYC inhibitors with chemotherapy, radiotherapy, or immunotherapy demonstrate synergistic potential. This article advocates for a multi-dimensional, biomarker-guided approach to MYC targeting, emphasizing rational drug combinations and continued innovation to overcome resistance and improve outcomes in MYC-driven cancers.
- |||||||||| Ibrance (palbociclib) / Pfizer, Kisqali (ribociclib) / Novartis
Review, Journal: Mechanistic Roles of Transcriptional Cyclin-Dependent Kinases in Oncogenesis: Implications for Cancer Therapy. (Pubmed Central) - May 14, 2025
Even with significant advancements, creating selective inhibitors with negligible off-target effects is still difficult. This review highlights the need for more research to optimize therapeutic strategies and improve patient outcomes by giving a thorough overview of the non-transcriptional roles of CDKs in cancer biology, their therapeutic potential, and the difficulties in targeting these kinases for cancer treatment.
- |||||||||| tambiciclib (SLS009) / SELLAS Life Sciences
In vitro efficacy of CDK9 inhibitor tambiciclib (SLS009) in ASXL1 mutated colorectal cancer cell lines. (Hall A - Posters and Exhibits; Poster Bd #: 436) - Apr 23, 2025 - Abstract #ASCO2025ASCO_3615;
This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population. Results indicate that ASXL1 mutations may be oncogenic drivers in some solid tumors, like CRC MSI-H, similar to those in AML and that efficacy of CDK9 inhibition with SLS009 may be similar in some solid tumors to the efficacy observed in AML.
- |||||||||| Journal: Self-awareness of retrosynthesis via chemically inspired contrastive learning for reinforced molecule generation. (Pubmed Central) - Apr 21, 2025
Experimental results show that our model could generate 100% valid and novel structures and also exhibits superior performance in generating molecules with fewer structural alerts against several baselines. More importantly, the molecules generated by our proposed model show potent biological activities against ataxia telangiectasia and Rad3-related (ATR) and cyclin-dependent kinase 9 (CDK9) targets in wet-lab experiments.
- |||||||||| Journal: Targeted degradation of CDK9 potently disrupts the MYC-regulated network. (Pubmed Central) - Apr 18, 2025
Importantly, degradation is more effective at disrupting MYC transcriptional regulation and subsequently destabilizing nucleolar homeostasis, likely by abrogation of both enzymatic and scaffolding functions of CDK9. These findings suggest that CDK9 degradation offers a more robust strategy to overcome limitations associated with its inhibition.
- |||||||||| zotiraciclib (TG02) / Cothera Biosci
Journal: Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib. (Pubmed Central) - Apr 17, 2025
P1/2
We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141).
- |||||||||| Journal: Drug design for cyclin-dependent kinase 9 (CDK9) inhibitors in silico. (Pubmed Central) - Apr 15, 2025
As expected, this combination exerted an additive inhibitory effect on CDK9 expression. These findings confirm the presence of a CDK9 hidden cavity that was revealed transiently by MD simulations, thus providing promising evidence for the development of CDK9 inhibitors.
- |||||||||| Journal: An eRNA transcription checkpoint for diverse signal-dependent enhancer activation programs. (Pubmed Central) - Apr 10, 2025
Overcoming this checkpoint for signal-dependent enhancer activation occurs in diverse pathways, including estrogen receptor-?, NF-?B-regulated proinflammatory stimulation, androgen receptor and neuronal depolarization. Therefore, a specific strategy required to convert a basal state enhancer P-TEFb complex to an active state to release a conserved checkpoint is apparently employed by several functionally important signal-regulated regulatory enhancers to implement the instructions of the endocrine and paracrine system.
- |||||||||| Journal: Dynamic O-GlcNAcylation and phosphorylation attract and expel proteins from RNA polymerase II to regulate mRNA maturation. (Pubmed Central) - Apr 5, 2025
We show that dynamic O-GlcNAcylation is a negative regulator of mRNA biosynthesis and propose that the addition and removal of the modification serve as quality control-steps to ascertain successful generation of mature mRNAs. Our work identifies unprecedented redundancy in the regulation of RNA Pol II, which increases resilience towards transcriptional stress, and also underscores the difficulty of targeting transcription to control cancer.
- |||||||||| Journal: Targeting processive transcription for Myc-driven circuitry in medulloblastoma. (Pubmed Central) - Apr 1, 2025
CDK9 inhibitor treatment depletes Myc-driven transcriptional programs, leading to potent anti-tumor effect in vitro and prolongation of xenograft survival in vivo . With a large number of CDK9 inhibitory compounds now in clinical development, this study highlights the opportunity for clinical translation of these for children diagnosed with Myc-MB.
- |||||||||| Preclinical development of a novel small molecule multitarget inhibitor LCI133 for endometrial adenocarcinoma (Section 21; Poster Board No: 19) - Mar 25, 2025 - Abstract #AACR2025AACR_9219;
With a large number of CDK9 inhibitory compounds now in clinical development, this study highlights the opportunity for clinical translation of these for children diagnosed with Myc-MB. In silico-designed LCI133, as a highly selective inhibitor against CDK4/6-CDK9-AURK with nano-molar potency and favorable PK/ADME properties, demonstrated promising in vivo therapeutic index in immunocompetent mouse models.
- |||||||||| BTX-A51 / Edgewood Oncology
Preclinical efficacy of the CK1 alpha/CDK7/CDK9 inhibitor BTX-A51 in CIC-rearranged sarcoma (Section 24; Poster Board No: 3) - Mar 25, 2025 - Abstract #AACR2025AACR_9031;
Treatment with BTX-A51 induces caspase 3-mediated apoptotic cell death through combined stabilization of p53 and inactivation of oncogenic drivers. Together with ongoing in vivo studies, our data will provide a compelling preclinical rationale for the evaluation of BTX-A51 in patients with CIC-rearranged sarcoma.
- |||||||||| Chemical probe discovery for PAX3::FOXO1 via small-molecule microarrays (Section 26; Poster Board No: 20) - Mar 25, 2025 - Abstract #AACR2025AACR_8840;
We then developed functional recombinant P3F protein production and purification in our lab to enable pure protein based assays. We hope our research strategy can further advance the current progress on targeting the conventionally undruggable P3F oncogenic fusion and bring insight to targeting disordered oncogenic fusions in other pediatric cancers.
- |||||||||| istisociclib (KB-0742) / Kronos Bio, enitociclib (VIP152) / Vincerx, zemirciclib (AZD4573) / AstraZeneca
Organoid-based drug screening identifies CDK9 as a target for stratified treatment of high-grade serous ovarian cancer (Section 4; Poster Board No: 22) - Mar 25, 2025 - Abstract #AACR2025AACR_8496;
For instance, expression of phosphodiesterase 3B (PDE3B) was correlated with CDK9i resistance (Pearson r = -0.744, p<0.001), while expression of ERBB3 was correlated with increased CDK9i sensitivity (Pearson r = 0.841, p<0.0001).Taken together, we demonstrate the application of an HGSC organoid biobank for identifying patient-specific targets, exceptional responder groups and potential CDK9i sensitivity biomarkers in HGSC. Results of this project could serve as a basis for designing a molecularly stratified CDK9 inhibitor-focused clinical trial in refractory HGSC patients.
- |||||||||| TY-1781 / TYK Medicines
TY-1781, a potent and highly selective CDK2 inhibitor, demonstrates superior anti-tumor activity in CCNE1 high-expression solid tumor models (Section 10; Poster Board No: 12) - Mar 25, 2025 - Abstract #AACR2025AACR_8278;
Taken together, we identified a highly selective and potent CDK2 inhibitor through medicinal chemistry screening and rounds of refining. The data suggest that TY-1781 may be eligible for further clinical development for Cyclin E1 high-expression patients who relapse from previous standard of care treatments.# Chengshan Niu and Meihua Li contributed equally to this work.*To Whom Correspondence should be addressed to Shaoqing Chen, Chengshan Niu, Meihua Li and Jun Li.
- |||||||||| 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.
- |||||||||| High-throughput screening reveals novel synergistic drug combinations for metastatic castration-resistant prostate cancer (Section 22; Poster Board No: 4) - Mar 25, 2025 - Abstract #AACR2025AACR_7935;
Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, with patients often developing resistance to androgen receptor (AR)-axis-targeted therapies such as Abiraterone and Enzalutamide...These results guided the development of a novel triple combination therapy to simultaneously target CDK9-regulated productive RNA polymerase II phosphorylation (Enitociclib), BRD4-mediated epigenetic remodeling (Pelabresib), and pro-survival BcL-xL (Navitoclax)...These findings provide a strong rationale for clinical development of multi-drug targeted combination regimens to overcome AR-V7-driven resistance and deliver durable responses with reduced toxicity for mCRPC patients with limited treatment options. Our approach also highlights the power of HTS to unbiasedly innovate synergistic therapies while uncovering critical biological mechanisms underlying cancer drug resistance.
- |||||||||| An isogenic CRISPR screen identifies novel MYC-driven vulnerabilities (Section 9; Poster Board No: 5) - Mar 25, 2025 - Abstract #AACR2025AACR_7108;
Excitingly, previously underexplored targets were identified with promising validation to-date. Together, this work features two successful strategies to prioritize hits from hundreds of synthetic-lethal genome-wide CRISPR screens to identify novel MYC-driven vulnerabilities in cancer.
- |||||||||| THAL-SNS-032 - Dana / Farber Cancer Institute
Cyclin-dependent kinase signaling in oncology: assessing the effectiveness of a CDK9-targeting using no-wash immunoassays (Section 12; Poster Board No: 8) - Mar 25, 2025 - Abstract #AACR2025AACR_7061;
Together, this work features two successful strategies to prioritize hits from hundreds of synthetic-lethal genome-wide CRISPR screens to identify novel MYC-driven vulnerabilities in cancer. 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 1
- |||||||||| Ibrance (palbociclib) / Pfizer
A highly selective CDK4/9 dual inhibitor reverses tumor resistance to CDK4/6 inhibitors (Section 35; Poster Board No: 3) - Mar 25, 2025 - Abstract #AACR2025AACR_6662;
The use of CDK4/9 inhibitors N049 could be an effective strategy to address resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. CDK4/9 inhibitors N049 represent a promising therapeutic approach for overcoming breast cancer resistance.
- |||||||||| CHAC1 regulates paraptosis by promoting glutathione degradation in cancer cells (Section 13; Poster Board No: 8) - Mar 25, 2025 - Abstract #AACR2025AACR_5792;
CHAC1 enhances the degradation of GSH, resulting in a decline in the GSH/GSSG ratio, a more oxidized intracellular state, and increased ROS production. This leads to the disruption of proteostasis, ultimately inducing paraptosis.
- |||||||||| VB18214 / Shenzhen Yangli Pharma, tagtociclib (PF-07104091) / Pfizer
Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy (Section 20; Poster Board No: 22) - Mar 25, 2025 - Abstract #AACR2025AACR_5620;
Compared to the clinically advanced CDK2 inhibitor PF-07104091, VB18214 demonstrated 5-fold greater potency in inhibiting CDK2 kinase activity, 16-fold higher affinity for CDK2 in NanoBRET assays, 2-fold greater selectivity over CDK1 in both biochemical and intracellular assays, and 9-fold higher antiproliferative activity in OVCAR3 cells.These findings position VB18214 as a potent and selective CDK2 inhibitor with significant potential for clinical development in cancers driven by CDK2/cyclin E dysregulation, as well as CDK4/6 treatment progressed mBC. More characterization data for VB18214 will be updated at the meeting.
- |||||||||| OBP-004 / OncoBone Therapeutics
A highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor burden in bone, brain, lung and lymph nodes and decreases growth of triple-negative breast cancer cells in bone (Section 20; Poster Board No: 13) - Mar 25, 2025 - Abstract #AACR2025AACR_5613;
In the MV4-11 model, OBP-004 showed strong decrease of bone, brain, lung and lymph node metastases. In the intratibial 4T1 model, OBP-004 decreased tumor growth in bone from day 10 forward, bone pain at day 14, and cancer-induced bone loss at day 21.We conclude that the highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor growth in bone, brain, lung and lymph nodes and decreases metastatic growth of TNBC cells in bone microenvironment, bone pain and cancer-induced bone loss in an aggressive preclinical TNBC model.
- |||||||||| Efficacy of novel CDK9/CDK4/6/PI3K triple inhibitors, LCI133 and LCI139, in Ewing sarcoma (Section 20; Poster Board No: 7) - Mar 25, 2025 - Abstract #AACR2025AACR_5604;
This is a promising potential treatment strategy for ES patients for whom new treatment approaches are desperately needed. These studies provide preclinical evidence of the potential efficacy of small molecule MKIs in ES and support the future efforts of in vivo models evaluating efficacy and safety of these agents.
- |||||||||| orludodstat (BAY2402234) / Bayer, brequinar (DUP 785) / BMS, Clear Creek Bio, dinaciclib (MK-7965) / Merck (MSD)
Inhibition of pyrimidine synthesis and the cell cycle in mesothelioma (Section 19; Poster Board No: 25) - Mar 25, 2025 - Abstract #AACR2025AACR_5593;
These studies provide preclinical evidence of the potential efficacy of small molecule MKIs in ES and support the future efforts of in vivo models evaluating efficacy and safety of these agents. BAY2402234 is an extremely potent inhibitor of cell growth in multiple mesothelioma cell lines and 59-1,881 times more potent than brequinar; 2) BAY2402234 and dinaciclib act synergistically, suggesting an interaction between pyrimidine biosynthesis and one or more of the following CDKs: CDK1, CDK2, CDK5, and/or CDK9; and 3) BAY2402234 results in increased PD-L1 expression and increased cytokine pathway mRNA expression, suggesting the potential for enhancement of immune checkpoint blockade.
- |||||||||| ORI-15412 / Origenis
Mastering metastases by novel selective CDK9 Inhibitor ORI-15412 (Section 21; Poster Board No: 7) - Mar 25, 2025 - Abstract #AACR2025AACR_4351;
The drug was well-tolerated with no observed toxicity, and efficacy was dose-dependent, underscoring its potential for treating metastatic cancers. Having completed all IND-enabling safety and toxicity studies with NOAEL at efficacious doses, ORI-15412 is positioned as a clinical-ready candidate, offering a promising new approach for patients with metastatic cancers, particularly those with brain and bone involvement.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, dinaciclib (MK-7965) / Merck (MSD)
CDK9 inhibition enhances apoptosis of TP53 mutated AML when combined with standard chemotherapy (Section 17; Poster Board No: 13) - Mar 25, 2025 - Abstract #AACR2025AACR_4314;
These results suggest that inhibition of CDK9 sensitizes AML cells independently of TP53, with less pronounced cytotoxicity in normal PBMCs of healthy donors. We plan to further examine the effect of CDK9 inhibition using a highly selective CDK9 inhibitor and validate these results with primary AML and normal bone marrow samples.
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