zemirciclib (AZD4573) / AstraZeneca - LARVOL DELTA

MYC networks associate with decreased CD8 T-cell presence in diffuse large B-cell lymphoma and may be addressed by the synergistic combination of AZD4573 and Selinexor - a preliminary analysis. (PubMed, Ann Hematol) - "In vitro application of the CDK9 inhibitor AZD4573 and XPO1 inhibitor Selinexor significantly reduced DLBCL cell line viability as single agents and produced synergistic results when applied in combination. Our analysis presents key associations between the MYC oncogene and depleted TME presence capable of providing clarity within the evolving precision CAR-T treatment landscape."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD58 • CD8 • IL7R • MYC • PD-L2

Inhibition of Cyclin-Dependent Kinase 9 Rapidly Induces Apoptosis in Acute Lymphoblastic Leukemia and Shows Synergistic Activity with BH3-Mimetics (ASH 2024) - "Using the multi-CDK inhibitor dinaciclib, which targets CDK1, 2, 5 and 9, and the specific CDK9 inhibitor AZD4573, we analyzed the effects of both inhibitors in a series of ALL cell lines (BCP-ALL n=10, T-ALL n=6) and primary, patient-derived xenograft (PDX) samples (BCP-ALL n=15, T-ALL n=9)...Based on this, we investigated combinatorial inhibition of CDK9 (AZD4573) together with inhibitors of BCL-2 or BCL-XL (venetoclax, A-1331852, AZD4320) using dose-response matrix analyses and found enhanced cell death and synergistic activity for both combinations...However, intrinsic insensitivity due to dysbalanced protein levels of pro-survival proteins might limit efficacy. Combining CDK9 inhibition with inhibitors of the anti-apoptotic molecules BCL-2/BCL-XL significantly enhances cell death, thus overcoming insensitivity and providing an effective, novel therapeutic anti-ALL strategy to be further evaluated for clinical application."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • BCL2L1 • CASP3 • CDK1 • CDK9 • MCL1

CDK9 Is a Vulnerability in GATA-3 Driven and MCL-1 Independent T-Cell Lymphomas (ASH 2024) - "Methods : A pharmacologic strategy, using the selective CDK9 inhibitor AZD4573, was utilized to identify CDK9 dependent transcripts...Furthermore, CDK9 and GATA-3 are binding partners, and CDK9 inhibition significantly impaired transcription of the GATA-3 dependent transcriptome. Therefore, CDK9 inhibition, by impairing expression of the GATA-3 dependent transcriptome, is an attractive therapeutic strategy for GATA-3 driven TCL, many of which are largely resistant to conventional chemotherapeutic approaches."

Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CDK9 • GATA3 • MCL1 • PTEN • SMARCB1 • TP53

Orally Effective CDK9 Inhibitor YX0798 for Treating Aggressive Lymphoma (ASH 2024) - "We also showed AZD4573 and enitociclib are safe and effective treatments in preclinical MCL models, and the therapeutics target CDK9. 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."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDC37 • HSP90AA1 • MCL1 • MYC

Combinatorial Therapy of CDK9 Inhibitor with CD19 CAR-T to Reciprocally Overcome Therapy Resistance and Enhance Treatment Efficacies Against Aggressive B-Cell Lymphomas (ASH 2024) - "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."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition. (PubMed, Cancer Cell Int) - "We also conducted in vivo studies in a leukemic xenograft model, where AZD4573 treatment led to significant tumor regression, decreased ATAT1 expression, and α-tubulin degradation. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts α-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors."

Journal • Hematological Disorders • Hematological Malignancies • Oncology

Differential activity of specific inhibitors of transcription regulating cyclin-dependent kinases in thyroid cancer cells (ATA 2024) - "Methods and We selected thyroid cancer cell lines with a variety of genetic drivers for initial screening studies with CDK7/ 12/13 (THZ1) and CDK9 (AZD4573) inhibitors... These data suggest that speci fic inhibitors of CDK12/13, and CDK9, are capable of inhibiting thyroid cancer growth and inducing apoptosis. Further studies evaluating the potential ef ficacy of these more speci fic inhibitors are warranted in thyroid cancer."

Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • CDK12 • CDK9 • RET

Repurposing SSRI/SNRI targeting neurotransmitter signaling to overcome resistance to CDK9 inhibitors in diffuse midline glioma (SNO 2024) - "Cyclin-dependent kinase 9 (CDK9i) inhibitors such as zotiraciclib (ZTR) are in clinical trials for glioma, but CDK9i treatment alone may be ineffective due to the development of resistance...Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres by BLISS analysis and show that co-treatment with CDK9i and SSRI/SNRI strongly induces the apoptotic marker cleaved caspase 3 and reduces the CDK9 target phos-Pol2Ser2...Finally, preclinical studies show that co-treatment with low doses of AZD4573 and sertraline reduces the growth of orthotopic DMG xenografts and prolongs overall survival. Taken together, these data suggest that SSRI/SNRI and CDK9i might be used in combination to synergistically reduce DMG growth and overcome CDK9i resistance."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • CASP3 • CDK9

Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development. (PubMed, Bioorg Med Chem Lett) - "YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900)."

Journal • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Mechanisms and efficacy of small molecule "latency promoting agents" to inhibit HIV reactivation ex vivo. (PubMed, JCI Insight) - "While some drugs primarily inhibited one or two steps in HIV reactivation, other drugs (CDK inhibitors, splicing inhibitors, tanespimycin, and triptolide) inhibited multiple stages of HIV transcription and blocked the production of supernatant viral RNA. Dinaciclib, AZD4573, and pladienolide B also appeared to inhibit HIV splicing in unstimulated PBMC. By selecting drugs with known mechanisms of action, we specifically identified cellular factors and pathways that may be involved in regulation of HIV expression. These drugs/targets deserve further study in strategies aimed at reducing HIV-associated immune activation or achieving a functional cure."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Cyclin dependent kinase 9 inhibition reduced programmed death-ligand 1 expression and improved treatment efficacy in hepatocellular carcinoma. (PubMed, Heliyon) - "CDK9 inhibitors AZD4573 and atuveciclib reduced the IFN-γ induced PD-L1 expression in a dose-dependent manner. In conclusion, CDK9 inhibition could reduce the expression of PD-L1 in HCC cells. Using both CDK9 inhibitors and anti-PD-L1 antibodies is more effective than using either agent alone."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CDK9 • IFNG • PD-L1

In silico design of novel multitarget small molecule inhibitors to treat PTEN-mutant endometrial carcinoma. (ASCO 2024) - "Triple PI3K-CDK4/6-CDK9 inhibitor, LCI139, is nanomolar potent against PTEN mutant EC cell lines + displays decreased toxicity compared with CDK9 inhibitor reference compounds, AZD4573 + flavopiridol. Our results merit mechanistic dissection of PTEN interaction with PI3K + CDK9 signaling pathways, cell cycle machinery, CDK9-mediated transcriptional control. These data support extensive in vivo potency, toxicity, PK/PD studies to assess LCI139's clinical utility in treating EC."

Endometrial Cancer • Oncology • Solid Tumor • ANXA5 • CDK6 • MCL1 • PIK3CA • PIK3CD • PIK3CG • PTEN

Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations (AACR 2024) - "AZD4573 is a highly potent and selective Cyclin-Dependent Kinase 9 inhibitor...Dosing patients already experiencing higher liver stress levels may be more susceptible to drug-induced ALT and bilirubin elevation, and patients with increasing in-study liver stress may only present at later doses. This work demonstrates metabolomics utility to elucidate possible mechanisms of liver toxicity as well as to identify potential predictive biomarkers for further investigation to explore individual patient risk in clinical studies."

Biomarker • Clinical • Oncology • CDK9

Proteomic evaluation of combination data in acute myeloid leukemia to inform mechanism of action and new targets (AACR 2024) - "In the proteomics evaluation study, MOLM13 cells treated for 7 days under different conditions - (1) vehicle control; (2) cytarabine alone; (3) decitabine alone; (4) venetoclax alone; (5) AZD4573 alone; (6) AZD4573+cytarabine; (7) AZD4573+decitabine; (8) AZD4573+venetoclax - were collected for proteomics analysis using LC-MS/MS...Interestingly, targeting AURKB with AZD2811 has been shown to overcome venetoclax resistance in AML... Our proteomics analysis identifies vulnerable and resistant pathways and proteins, shedding light on the mechanism of action and revealing potential new targets for AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AURKB • CDK9 • PHGDH

Targeting CDK9 in cutaneous T-cell lymphoma using patient-derived xenograft models (AACR 2024) - "In addition, the expression level of MCL-1 appeared to be correlated with the ex vivo anti-tumor activity of AZD4573. Our findings provide a rationale for clinical investigation of targeting CDK9 in CTCL."

Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • ANXA5 • CASP3 • CASP7 • CD2 • CDK9 • MCL1

AZD4573 in combination with CHOP increases combination benefit in preclinical peripheral T-cell lymphoma models (AACR 2024) - "Using MCL-1 inhibitor AZD5991, we showed statistically significant benefit in survival when combined with CHOP in MCL-1 dependent preclinical pTCL PDX models (Koch et al. CHOP treatment in vitro resulted in a decrease in c-MYC levels but not MCL-1, suggesting that combination benefit may be driven through c-MYC. This data suggests that treatment with AZD4573 as a monotherapy or in combination with CHOP regimen ­would be an effective therapeutic strategy in pTCL."

Combination therapy • IO biomarker • Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2A1 • BCL2L1 • CASP3 • CASP7 • MYC

In silico design of novel multitarget small molecule inhibitor LCI139 for the treatment of PTEN-mutant endometrial carcinoma (AACR 2024) - "Triple PI3K-CDK4/6-CDK9 inhibitor, LCI139, is nanomolar potent against PTEN mutant EC cell lines and displays decreased toxicity compared with CDK9 inhibitor reference compounds, AZD4573 and flavopiridol. Our results merit further mechanistic dissection of PTEN interaction with PI3K pathway signaling, cell cycle machinery, CDK9-mediated transcriptional control. These data support extensive in vivo potency, toxicity, PK/PD studies to assess LCI139's clinical utility in treating EC."

Endometrial Cancer • Oncology • Solid Tumor • ANXA5 • CDK6 • MCL1 • PIK3CA • PIK3CD • PIK3CG • PTEN

CDK9 inhibitors modulate the transcriptional landscape of colorectal cancer to suppress MAPK signaling and synergizes with BRAF inhibitors to treat BRAF-mutant colorectal cancer (AACR 2024) - "Cyclin-dependent kinase 9 (CDK9) is a key activator of RNA Pol II transcription and promotes the expression of many cancer driver genes, making CDK9 a promising target for cancer therapy. Human CRC cell lines, patient-derived organoids (PDOs), cell line xenografts, and patient-derived xenografts were used to investigate the efficacy and mechanisms of action of the CDK9 inhibitors AZD4573, enitociclib, and NVP-2, as well as the BRAF inhibitors encorafenib and dabrafenib. We have found CDK9 inhibitors to potently suppress CRC growth and survival through a unique mechanism of action, by vertical suppression of the MAPK signaling pathway. We demonstrate that CDK9 inhibitors can synergize with BRAF inhibitors in the treatment of BRAF-mutant CRC models. Thus, CDK9 inhibitors are a promising class of drugs warranting further investigation, including early-phase clinical trials, in mCRC."

Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Solid Tumor • EGFR • KRAS • MYC

Application of high-grade serous ovarian cancer organoids in functional precision medicine (AACR 2024) - "In several patients, we observed a pronounced cytotoxicity of several cyclin-dependent kinase (CDK) inhibitors, all of which potently inhibit CDK9, including two selective inhibitors (AZD4573 and VIP152) in clinical development. A platform for efficient establishment and drug-response profiling of high-grade serous ovarian cancer organoids. Developmental Cell (2023)"

Hematological Malignancies • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2

Targeting CDK9 with a novel potent and selective inhibitor, YX0798, in CAR-T-relapsed mantle cell lymphoma models (AACR 2024) - "Targeting CDK9 with its inhibitors AZD4573 and enitociclib is safe and effective for treatment in preclinical MCL models, and they are currently under clinical investigation to assess their efficacy and safety. This treatment efficacy was found to be similar at that of AZD4573 but at a higher dosage (15+15 mg/kg, 2 hours split, QW, IP). No adverse effects in mice were observed for any of treatments.ConclusionThese data show that our novel CDK9 inhibitor YX0798 is potent and efficacious in treating aggressive MCL models and overcame CAR-T resistance at a lower dosage than AZD4573."

IO biomarker • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • CDK9 • MCL1 • MYC

AZD4573 as Monotherapy or in Combinations With Anti-cancer Agents in Patients With r/r PTCL or r/r cHL (clinicaltrials.gov) - P2 | N=52 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Feb 2024

Combination therapy • Monotherapy • Trial completion • Trial completion date • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

CDK9 Inhibition Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma (MCL) (ASH 2023) - "IACS-010759, an inhibitor of complex I of the ETC which targets OxPhos, demonstrated synergy with AZD4573 in parental and ibr-resistant MCL cell lines. CDK9 inhibition with AZD4573 induced apoptosis, downregulated MYC and MCL1 and NFκB signaling, and overcame ibr resistance in preclinical MCL models. 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."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CD40LG • CD5 • MYC • PTPRC • TGFB1 • TNFA

The Novel CDK9/CDK4/6/PI3K Triple Inhibitor LCI139 for the Treatment of MYC-Driven Mantle Cell Lymphoma (ASH 2023) - "Compared with clinical single agent CDK9 inhibitor AZD4573, LCI139 is less toxic to normal human stromal cells (HS-5), whereas both LCI139 and AZD4573 have no significant cytotoxic effect on normal human foreskin fibroblast cells (Hs68). 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."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • ANXA5 • CCND1 • CDK9 • MYC • PARP1 • PIK3CA • PIK3CG

Transient CDK9 Inhibition with AZD4573 Effectively Induces Apoptosis in Burkitt Lymphoma As a Monotherapy in Pre-Clinical Models (ASH 2023) - 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."

Monotherapy • Preclinical • Burkitt Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2L1 • CASP3 • MCL1 • MYC

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 (ASH 2023) - "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."

Biomarker • IO biomarker • Tumor microenvironment • Diffuse Large B Cell Lymphoma • Oncology • CD4 • CD8 • CDK9 • CDKN1A • TNFAIP3 • XPO1