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- zemirciclib (AZD4573) / AstraZeneca
AZD4573 in Combination with CHOP Increases Combination Benefit in Preclinical Peripheral T-Cell Lymphomas Models () - Dec 2, 2023 - Abstract #ASH2023ASH_9062;
P2
Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E and for CD30-postive pTCLs, brentuximab vedotin is approved...Using the MCL-1 inhibitor AZD5991, we have shown statistically significant benefit in survival when combined with CHOP in 2 MCL-1 dependent preclinical pTCL PDX models (Koch et al...These data suggested that treatment with AD4573 either as a monotherapy or in combination with CHOP, would be an effective therapeutic strategy in pTCL. AZD4573 monotherapy is currently being evaluated in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK in patients with relapsed/refractory pTCL.
- PRT2527 / Prelude Therap
A Phase 1 Study Evaluating PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Select Relapsed/Refractory B-Cell Malignancies () - Dec 2, 2023 - Abstract #ASH2023ASH_8255;
P1
The study is open to enrollment and registered at ClinicalTrials. gov (NCT05665530).
- PRT2527 / Prelude Therap
PRT2527, a Novel Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, Has Potent Antitumor Activity in Combination with BTK and BCL2 Inhibition in Various Lymphoid Malignancies () - Dec 2, 2023 - Abstract #ASH2023ASH_7717;
P1
Further work characterizing PRT2527 as monotherapy and in combination with BTKi and BCL2i in in vivo models of BTKi-resistant MCL and CLL is currently ongoing. Altogether these data provide a rationale for evaluating PRT2527 in combination with BTK and BCL2 inhibitors for the treatment of patients with relapsed/refractory hematologic malignancies.
- Suppression of Microtubule Acetylation Mediates Theanti-Leukemic Effect of CDK9 Inhibition () - Dec 2, 2023 - Abstract #ASH2023ASH_7706;
Mechanically, we identified that CDK9 inhibition downregulated the expression of ATAT1, the acetyltransferase responsible for ?-tubulin acetylation, further compromising microtubule stability. 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.
- pinometostat (EPZ-5676) / Ipsen, VTP-50469 / Syndax Pharma, zemirciclib (AZD4573) / AstraZeneca
Variable Response of MLL-Rearranged Leukemia Cell Lines to Combinations of Menin, CDK9 and DOT1L Inhibitors () - Dec 2, 2023 - Abstract #ASH2023ASH_7681;
The varying responses of different MLL-r leukemia cell lines to drug combination treatment indicate that not all cases of MLL-r leukemia will respond uniformly to treatment combinations. Taken together, our data provide a strategy to determine optimal treatment combinations for personalized treatment of MLL-r leukemia.
- | Tagrisso (osimertinib) / AstraZeneca
Journal: Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer. (Pubmed Central) - Nov 27, 2023
Furthermore, Z11 demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall, Z11 served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.
- | KB-0742 / Kronos Bio
Journal: Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers. (Pubmed Central) - Nov 15, 2023
Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.
- | enitociclib (VIP152) / Vincerx
Journal: Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription. (Pubmed Central) - Nov 15, 2023
An unbiased analysis of the genes affected by CDK9 inhibition in both cell lines demonstrates that RNA polymerase II and transcription pathways are primarily affected and novel enitociclib targets such as PHF23 and TP53RK are discovered. These findings are recapitulated in blood samples from enitociclib-treated patients; while MYC downregulation is most robust with enitociclib treatment, other CDK9 regulated targets may be MYC independent delivering a transcriptional downregulation via RNA polymerase II.
- zotiraciclib (TG02) / Cothera Biosci
Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: final results of the EORTC 1608 STEAM trial (Exhibit Hall A/B) - Nov 11, 2023 - Abstract #SNO2023SNO_563;
P1
Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.
- | Journal: Spt5 C-terminal repeat domain phosphorylation and length negatively regulate heterochromatin through distinct mechanisms. (Pubmed Central) - Nov 8, 2023
This separation of function argues that Spt5 CTD phosphorylation and CTD length restrict heterochromatin through unique mechanisms. More broadly, our findings argue that length and phosphorylation of the Spt5 CTD repeat array have distinct regulatory effects on transcription.
- KB-0742 / Kronos Bio
A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in triple negative breast cancer and transcriptionally addicted relapsed or refractory solid tumors (Hall 2-3) - Nov 4, 2023 - Abstract #SABCS2023SABCS_1577;
P1/2
Target accrual: Targeted total enrollment is 170 patients. For additional information, contact clinicaltrials@kronosbio.com
- zemirciclib (AZD4573) / AstraZeneca
Transient CDK9 Inhibition with AZD4573 Effectively Induces Apoptosis in Burkitt Lymphoma As a Monotherapy in Pre-Clinical Models (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_6479;
P2
AZD4573 is currently in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK of AZD4573 in patients with relapsed or refractory Peripheral T-cell lymphomas (pTCL). Our findings demonstrate that targeting CDK9 with AZD4573 can effectively induce apoptosis in pre-clinical BL models and could be an effective therapy for BL patients.
- enitociclib (VIP152) / Vincerx
Targeting CDK9 in KMT2A-Rearranged Infant Leukemia: Evidence for Activity and Drug Synergy with Enitociclib (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5728;
Our findings demonstrate that targeting CDK9 with AZD4573 can effectively induce apoptosis in pre-clinical BL models and could be an effective therapy for BL patients. Enitociclib also potentiated the anti-leukemic effect of chemotherapies for childhood leukemia with the most effective combination observed with doxorubicin (0.01
- voruciclib (ME-522) / MEI
A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML) (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_5721;
P1
There was no significant myelosuppression in pts with B-cell malignancies. As the safety profile suggested non-overlapping toxicities with venetoclax, the study is now evaluating voruciclib in combination with venetoclax in pts with R/R AML to exploit dual inhibition of Bcl-2 and Mcl-1.
- Imbruvica (ibrutinib) / AbbVie, J&J, zemirciclib (AZD4573) / AstraZeneca
The Novel CDK9/CDK4/6/PI3K Triple Inhibitor LCI139 for the Treatment of MYC-Driven Mantle Cell Lymphoma (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_5610;
Finally, we show that LCI139 overcomes chronic ibrutinib resistance by decreasing viability in JeKO-1 IR and Mino IR cells with an IC50 of 79 nM and 89 nM, respectively. Therefore, the multitarget small molecule inhibitor LCI139 has superior potency against IR MCL cell lines and overcomes ibrutinib-resistance at nanomolar doses.
- Transcription Defects in SF3B1K700E Induce Targetable Alterations in the Chromatin Landscape (Marriott Marquis - Marriott Grand) - Nov 3, 2023 - Abstract #ASH2023ASH_4826;
Through an unbiased shRNA screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, improved the transcription defects and their downstream effects. Our findings shed light on the mechanisms by which oncogenic mutant spliceosomes affect chromatin organization through their effects on Pol II transcription elongation and present a rationale for targeting the Sin3/HDAC complex as a potential therapeutic strategy.
- Xpovio (selinexor) / Karyopharm, zemirciclib (AZD4573) / AstraZeneca
Cooperative Networks between MYC and XPO1 Associated with Decreased T-Cell Presence and a Depleted Tumor Microenvironment May be Addressed By the Synergistic Combination of AZD4573 and Selinexor (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_3944;
Our results support that the cooperation between MYC and XPO1 is associated with T-cell reductions characteristic of a Depleted or Cold TME, a key issue for CAR-T success. We applied the targeted therapies AZD4573 and Selinexor vs. cell line models to address this pathway, with both displaying anti-tumor effects as single agents.
- enitociclib (VIP152) / Vincerx
The Selective CDK9 Inhibitor VIP152 Overcame Therapeutic Resistance in Mantle Cell Lymphoma (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_3769;
Moreover, VIP152 markedly inhibited the growth of three patient-derived xenograft tumor models, overcoming BTKi resistance (P<0.001), BTKi-venetoclax dual resistance (P<0.01), and BTKi-CAR-T dual resistance (P<0.001). Conclusion These data showed that CDK9 was a promising target for treating MCL and using VIP152 to specifically target it was efficacious in overcoming a variety of therapeutic resistances in MCL.
- Clinical Characteristics, Treatment Patterns, and Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Refractory to Covalent Bruton's Tyrosine Kinase Inhibitor (BTKi) and Exposed to B-Cell Lymphoma 2 Inhibitor (BCL2i) (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_2338;
Overall response rates to treatment immediately after BTKi and BCL2i treatment are low among doubly refractory patients. More effective treatments are needed to address the unmet therapeutic needs of CLL/SLL patients who are refractory to both BTKi and BCL2i.
- Pre-Clinical Efficacy of CDK7 Inhibitor-Based Combinations in Cellular Models of Advanced Myeloproliferative Neoplasms (MPN) Transformed to AML (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_2205;
Treatment with JAK inhibitor (JAKi), e.g., ruxolitinib, venetoclax or hypomethylating agents alone or in combination are ineffective in improving the poor survival in MPN-sAML...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and clinical grade SY-5609, dose-dependently (20 to 250 nM) increased % G1 while reducing the % of cell-cycle S phase SET2 and HEL cells...SY-5609 treatment also exerted synergistic lethality with the BETi pelabresib or BD2-selective BETi ABBV-744 or the CBP/p300 inhibitor GNE-049 in MPN-sAML cells...Additionally, compared to each drug or vehicle control, co-treatment with SY-5609 and OTX015 (30 mg/kg/day by oral gavage) reduced more MPN-sAML burden and significantly improved survival in a HEL-Luc/GFP xenograft model without inducing toxicity. These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to further evaluate in vivo efficacy of CDK7i-based combinations against advanced MPN with excess blasts or MPN-sAML.
- Imbruvica (ibrutinib) / AbbVie, J&J
CDK9 Inhibition Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma (MCL) (Halls G-H (San Diego Convention Center)) - Nov 3, 2023 - Abstract #ASH2023ASH_2058;
This was also noted in a sample obtained from a clinical trial. Prolonged CDK9 inhibition led to metabolic reprogramming towards OxPhos, which thus can serve as a therapeutic target in MCL.
- indisulam (E7070) / Eisai, dinaciclib (MK-7965) / Merck (MSD)
Regulation of Alternative Splicing in B-Cell ALL By DYRK1A (Marriott Grand Ballroom 11-13 (Marriott Marquis San Diego Marina)) - Nov 3, 2023 - Abstract #ASH2023ASH_937;
Ectopic expression of RBM39 partially rescued the growth inhibition upon dinaciclib and EHT 1610 treatment suggesting downregulation of RBM39 is the key event in drug targeting. Together, our results reveal that DYRK1A controls RNA splicing by regulating the SF3B1-RNA Pol II interaction and that RBM39 is a therapeutic target in B-ALL.
- Bromodomain Protein BRD4 Is a Transcriptional Repressor of Terminal Erythropoiesis By Interacting with EHMT1/2 (SDCC - Room 25) - Nov 3, 2023 - Abstract #ASH2023ASH_900;
Together, our results reveal that DYRK1A controls RNA splicing by regulating the SF3B1-RNA Pol II interaction and that RBM39 is a therapeutic target in B-ALL. Taken together, our study demonstrated a non-classical role of BRD4 during terminal erythropoiesis, which provided a new and simple method to improve enucleation efficiency for red blood cells production from stem cells in vitro , and may also supply a therapeutic target to dyserythropoiesis by inducing maturation of erythrocyte progenitor cells.
- | Journal: A virtual screening investigation to identify bioactive natural compounds as potential inhibitors of cyclin-dependent kinase 9. (Pubmed Central) - Oct 30, 2023
Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.Communicated by Ramaswamy H. Sarma.
- | Journal: Allele-specific gene regulation, phenotypes, and therapeutic vulnerabilities in estrogen receptor alpha mutant endometrial cancer. (Pubmed Central) - Oct 22, 2023
Inhibition of these regulatory proteins resulted in decreased growth and migration, representing potential novel treatment strategies for ER mutant endometrial cancer. Implications: This study provides insight into mutant ER activity in endometrial cancer and identifies potential therapies for women with ER mutant endometrial cancer.
- | Lumakras (sotorasib) / Amgen
Journal: Discovery of highly potent and selective KRAS degraders by VHL-recruiting PROTACs for the treatment of tumors with KRAS-Mutation. (Pubmed Central) - Oct 18, 2023
Through drug design and structure optimization, a series of highly potent and selective KRAS Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032...Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRAS-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRAS-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.
- | Lynparza (olaparib) / Merck (MSD), AstraZeneca
Journal: Design, synthesis, and biological evaluation of novel 4,4'-bipyridine derivatives acting as CDK9-Cyclin T1 protein-protein interaction inhibitors against triple-negative breast cancer. (Pubmed Central) - Oct 15, 2023
Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRAS-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination. Moreover, the administration of B19 in combination with the PARP inhibitor Olaparib results in a significant increase of the antitumor activity in MDA-MB-231
- | Journal: Aminopyridone-linked benzimidazoles: a fragment-based drug design for the development of CDK9 inhibitors. (Pubmed Central) - Oct 6, 2023
Compound 6a arrested the cell cycle at S phase and induced apoptosis in MCF-7 cells. Compound 6a is a promising CDK9 inhibitor that warrants additional research for cancer treatment.
- AZD4573 / AstraZeneca
AZD 4573, a new selective CDK-9-inhibitor, displays high pro-apoptotic efficacy in AML cell models (Hall A) - Sep 30, 2023 - Abstract #DGHO2023DGHO_1289;
We provide a rationale for further evaluation of CDK-9 inhibition in acute myeloid leukemia, especially with Venetoclax resistance. Early clinical trials are ongoing.
- | THAL-SNS-032 - Dana / Farber Cancer Institute
Journal: Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs. (Pubmed Central) - Sep 29, 2023
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: Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases. (Pubmed Central) - Sep 28, 2023
In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.
- The novel small molecule multitarget inhibitor LCI133 sensitizes endometrial carcinoma to TRAIL-mediated apoptosis (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_375;
Conclusions Together, these data cast a new light on the clinical failure of TRAIL therapy and provide evidence for its utility in cancer. 9 Additionally, it underscores the need to fully evaluate targeted therapy mechanism of action and explore the ability of epigenetic regulator and kinase inhibitors to mitigate immune escape and potentiate therapeutic response.
- BLX-3030 / Biolexis Therap
Development of BLX-3030, a Potent, Selective, Orally Available CDK9i shows promise in Pancreatic Ductal Adenocarcinoma (PDAC) Models (Level 2, Exhibit Hall D) - Sep 22, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_715;
- Xospata (gilteritinib) / Astellas, AZD4573 / AstraZeneca
Coadministration of AZD 4573 and gilteritinib exhibits a potent activity in FLT3 inhibitor-sensitive and -resistant AML cells (Level 2, Exhibit Hall D) - Sep 22, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_668;
- | alvocidib (DSP-2033) / Sumitomo Pharma, dinaciclib (MK-7965) / Ligand, Merck (MSD)
Journal, Pan tumor: Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response. (Pubmed Central) - Sep 20, 2023
We also found that in a cohort of 46 patients with HB, high CDK9 tumour expression was significantly associated with poor prognosis. Our work proves the usefulness of computational methods trained on pan-cancer datasets to reposition drugs in rare paediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.
- | Journal: Degradation of CDK9 by Ubiquitin E3 Ligase STUB1 Regulates P-TEFb Level and Its Functions for Global Target Gene Expression within Mammalian Cells. (Pubmed Central) - Sep 20, 2023
Knockdown of STUB1 enhances CDK9 expression and thus P-TEFb complex formation that leads to global increase in RNA polymerase II CTD phosphorylation and transcriptional activation of diverse P-TEFb target genes. Thus, we describe an important functional role of STUB1 in regulation of transcription through modulation of overall level of P-TEFb complex formation within mammalian cells.
- | enitociclib (VIP152) / Vincerx
Journal: Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy. (Pubmed Central) - Sep 18, 2023
In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152...To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.
- | Journal: Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy. (Pubmed Central) - Sep 18, 2023
Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20
- BLX-3030 / Biolexis Therap
Development of BLX-3030, a Potent and Selective Inhibitor of CDK9 for the Treatment of N-MYC Driven NeuroEndocrine Prostate Cancers (NEPC). (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_654;
- PRT2527 / Prelude Therap
A phase 1 dose-escalation study of PRT2527, a cyclin-dependent kinase 9 (CDK9) inhibitor, in adult patients with advanced solid tumors: an updated analysis. (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_652;
- enitociclib (VIP152) / Vincerx
Evidence of TCR and BCR clonal dynamics with enitociclib monotherapy in patients with MYC+ non-Hodgkin lymphoma (NHL). (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_566;
- KB-0742 / Kronos Bio
A First-In-Human Study of CDK9 Inhibitor KB-0742 Demonstrates Evidence of Tolerability and Clinical Activity. (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_478;
- PRT3789 / Prelude Therap
Discovery of PRT3789, a first-in-class potent and selective SMARCA2 degrader in clinical trials for the treatment of patients with SMARCA4 mutated cancers. (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_433;
- Activity of Dual BET and CDK9 Inhibition in Pancreatic Ductal Adenocarcinoma Informed from KinderMiner Prediction. (LEVEL 2, EXHIBIT HALL D) - Sep 16, 2023 - Abstract #AACRNCIEORTC2023AACR_NCI_EORTC_315;
- | Journal: MYC promotes global transcription in part by controlling P-TEFb complex formation via DNA-binding independent inhibition of CDK9 SUMOylation. (Pubmed Central) - Sep 14, 2023
Furthermore, MYC's activity in enhancing global transcription positively contributes to its activity in promoting cell proliferation and transformation. Together, our study demonstrates that MYC promotes global transcription, at least in part, by promoting the formation of the active P-TEFb complex via a sequence-specific DNA-binding activity-independent manner.
- | Kisqali (ribociclib) / Novartis
Preclinical, Journal: Synthesis and In Vitro Anticancer Activity of Novel 4-Aryl-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridines Arrest Cell Cycle and Induce Cell Apoptosis by Inhibiting CDK2 and/or CDK9. (Pubmed Central) - Sep 13, 2023
Together, our study demonstrates that MYC promotes global transcription, at least in part, by promoting the formation of the active P-TEFb complex via a sequence-specific DNA-binding activity-independent manner. Compound 9a showed the highest anticancer activity with IC = 2.59
- | Journal: CDK9 Inhibitor Induces Apoptosis, Autophagy, and Suppression of Tumor Growth in Adult T-Cell Leukemia/Lymphoma. (Pubmed Central) - Sep 7, 2023
Finally, LY2857785 significantly decreased the growth of ATL tumor xenografts. These results suggest that LY2857785 induces cell death of ATL cells by MCL-1-dependent apoptosis and autophagy and has anti-tumor activity.
- | Journal: AFF4 globally affects the release of paused RNA polymerase II in HEL cells. (Pubmed Central) - Aug 27, 2023
Mechanistically, AFF4 promotes pause release likely by facilitating the binding of P-TEFb to Pol II. These results suggest that extent of the impact of AFF4 on pause release is likely to be context-dependent or cell-type dependent.
- | SNS-032 / Viracta Therap
Journal: Discovery of HyT-based Degraders of CDK9-Cyclin T1 Complex. (Pubmed Central) - Aug 24, 2023
In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader...Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders.
- | Journal: Design and optimization of selective and potent CDK9 inhibitors with flavonoid scaffold for the treatment of acute myeloid leukemia. (Pubmed Central) - Aug 22, 2023
Notably, 21a demonstrated significant inhibition of tumor growth in the Mv4-11 xenograft tumor model. These findings indicate that compound 21a holds promise as a potential candidate for treating AML.