atuveciclib (BAY 1143572) / Bayer - LARVOL DELTA

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

Enantioselective S-Alkylation of Sulfenamides by Phase-Transfer Catalysis. (PubMed, Angew Chem Int Ed Engl) - "Given that sulfoximines are a bioactive pharmacophore of ever-increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free-NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)-sulfoximine stereoisomer."

Journal

Cyclin-Dependent kinase 9 (CDK9) inhibitor Atuveciclib ameliorates Imiquimod-Induced Psoriasis-Like dermatitis in mice by inhibiting various inflammation factors via STAT3 signaling pathway. (PubMed, Int Immunopharmacol) - "Moreover, Atuveciclib interfered with the abnormal STAT3 signaling pathway through the inhibition of CDK9, which ultimately ameliorated psoriatic-like skin inflammation. These suggested that CDK9 inhibition is a potential strategy for batting psoriasis."

Journal • Preclinical • Review • Dermatitis • Dermatology • Dermatopathology • Immunology • Inflammation • Oncology • Psoriasis • CDK9 • IFNG • TNFA

Unraveling TIMP1: a multifaceted biomarker in colorectal cancer. (PubMed, Front Genet) - "Drug sensitivity analysis, conducted using the DepMap database, revealed that colorectal cancer cell lines exhibiting elevated levels of TIMP1 expression were more responsive to certain drugs, such as CC-90003, Pitavastatin, Atuveciclib, and CT7001, compared to those with low levels of TIMP1. Furthermore, TIMP1 expression was positively correlated with that of ferroptosis-related genes, such as GPX4 and HSPA5. TIMP1 can be used as a biomarker for colorectal cancer and is associated with the immunological microenvironment, drug sensitivity, and ferroptosis inhibition in this disease."

Biomarker • IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CXCL1 • CXCL10 • CXCL8 • GPX4 • HAVCR2 • HSPA5 • MMP1 • MMP3 • SPP1 • TIMP1

Cyclin dependent kinase 9 (CDK9) inhibition increased efficacy of programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma (HCC) through decreasing programmed death-ligand 1 (PD-L1) expression (AACR 2023) - "We thus examined the influence of CDK9 inhibition on the expression of PD-L1 in HCC and the potential of improving the efficacy of PD-1 blockade with the combination of CDK9 inhibitors. We first examined the influence of specific CDK9 inhibitors, AZD4573 and atuveciclib, on interferon-γ (IFN-γ) induced PD-L1 expression of human HCC cell lines HuH7 and Hep3B. We demonstrated that CDK9 inhibition could reduce the IFN-γ induced PD-L1 expression of HCC cells. Combination of CDK9 inhibitors and anti-PD-L1 antibodies was more effective than either therapy alone."

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

VIP152 IS A NOVEL CDK9 INHIBITOR WITH IMPROVED SELECTIVITY, TARGET MODULATION, AND CARDIAC SAFETY IN PATIENTS WITH LYMPHOMA (EHA 2022) - P1 | "To demonstrate the utility of a selective CDK9 inhibitor for treatment of hematologic patients with an unmet medical need such as high-grade B cell lymphoma (HGBL) and chronic lymphocytic leukemia who relapse or are refractory to ibrutinib and venetoclax (R/R CLL)...Differential expression (DE) analysis from VIP152, atuveciclib and KB-0742 treatment of 2 lymphoma cell lines by RNA seq is compared to DE of samples from 7 VIP152 treated HGBL patients...With high ATP, VIP152, AZD4573 and alvocidib maintain potency in low nM range, while fadraciclib and KB-0742 have 760 nM-1.7 µM IC50s...Selective transcriptional downregulation is observed with 30mg IV weekly. Samples from patients with DLBCL or CLL are sensitive to VIP152 and updated PK, PD and ctDNA dynamics from the ongoing phase 1 trials (NCT02635672, NCT04978779) will be presented."

Clinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • TP53

Cyclin Dependent Kinase 9 Inhibition as a Potential Treatment for Hepatocellular Carcinoma. (PubMed, Oncology) - "We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC."

Journal • Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Leukemia • Oncology • Solid Tumor • BIRC5 • CDK9 • MCL1 • MYC

Cyclin dependent kinase 9 inhibition as a potential treatment for hepatocellular carcinoma. (ASCO-GI 2022) - " The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, on cell viability and apoptosis in HCC cell lines were examined. We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC."

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • BIRC5 • CDK9 • MCL1 • MYC • XIAP

SETD5 Modulates Hematopoietic Stem Cells Homeostasis By Mediating RNA Polymerase II Pausing in Cooperation with HCF-1 (ASH 2021) - "Inhibition of the transition of paused Pol II in Setd5 CKO c-Kit + cells with BAY 1143572 (p-TEFb/CDK9 inhibitor) or JQ1 (Brd4 inhibitor) significantly suppressed S phases entry in Setd5 CKO LSK + cells, indicating that increased transition of paused Pol II to elongation mediated by Setd5 depletion could be a main cause for the exit of quiescence stage of Setd5 CKO HSC cells. In summary, we here demonstrate a critical role of Setd5 in HSC maintenance and provide a new insight into the mechanism of Setd5 in regulating HSC quiescence by pausing Pol II-mediated differential expression of cell cycle genes via HCF-1-SETD5-PAF1-Pol II axis. MK.L and YJ.C contributed equally to this work."

CNS Disorders • Developmental Disorders • Hematological Disorders • Psychiatry • Transplantation • BRD4

The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death. (PubMed, Anticancer Res) - "This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CFLAR • MCL1

Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer. (PubMed, J Med Chem) - "Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency. (PubMed, Biochem Pharmacol) - "To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro. Finally, we show that flavopiridol also inhibits spontaneous ex vivo viral RNA production in CD4+ T cells from donors with HIV. These results implicate CDK9 inhibition (in the absence of HDAC inhibition) as a potentially favorable property in the search for compounds that durably reinforce HIV latency."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4 • CDK9

Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion. (PubMed, Eur J Med Chem) - "Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration...Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

Application of sulfoximines in medicinal chemistry from 2013 to 2020. (PubMed, Eur J Med Chem) - "For example, at least three sulfoximine containing drugs BAY 1143572, BAY 1251152 and AZD6738 have entered the clinic. Despite the increasing interest in sulfoximines and their chemistry, the routine application of this structure in drug discovery is still hampered due to limited experience in physicochemical and in vitro parameters of sulfoximines. Therefore, we reviewed all relevant articles from 2013 to the present in terms of potency and pharmacokinetic properties in order to support the addition of the sulfoximine component to the toolbox of medicinal chemists."

Journal • Review

Anti-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia. (PubMed, Ther Adv Hematol) - "Here, we investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7, which may contribute to decreased MYC and MCL1 protein levels. Finally, the combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent-based treatment of T-PLL."

IO Biomarker • Journal • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia • FBXW7 • MCL1 • MYC

Cyclin-Dependent Kinase 9 (CDK9) Inhibitor Atuveciclib Suppresses Intervertebral Disk Degeneration via the Inhibition of the NF-κB Signaling Pathway. (PubMed, Front Cell Dev Biol) - "The rat IVDD model also proved that CDK9 inhibition attenuated IVDD, as validated using magnetic resonance imaging and immunohistochemistry. Taken together, CDK9 is a potential therapeutic target to prevent IVDD."

Journal • Inflammation • TNFA

CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. (PubMed, Cell Death Dis) - "Small-molecule drugs targeting the CDK9 kinase, dinaciclib, flavopiridol, roscovitine, AT-7519, SNS-032, and DRB, diminished MDM4 levels and activated p53 in A375 melanoma and MCF7 breast carcinoma cells with only a limited effect on MDM2...CDK9 inhibitor atuveciclib downregulated MDM4 and enhanced p53 activity induced by nutlin-3a, an inhibitor of p53-MDM2 interaction, and synergized with nutlin-3a in killing A375 melanoma cells. Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4."

Journal • Breast Cancer • Melanoma • Oncology • Solid Tumor • MDM4

[VIRTUAL] Increasing complexity: A practical synthetic approach to three dimensional, cyclic sulfoximines and first insights into their in vitro properties (ACS-Fall 2020) - "Nevertheless, four sulfoximine compounds (roniciclib, atuveciclib, BAY 1251152, AZD6738) have entered clinical evaluation of late and their promising physicochemical and DMPK properties were important triggers for their selection as clinical candidates.However, only limited literature on the synthesis of cyclic sulfoximines (3) and their properties is currently available. This presentation highlights a practical, safe approach for the synthesis of five- to seven-membered cyclic sulfoximines (3), which are currently underrepresented in drug discovery.To gain further knowledge of the medicinal chemistry properties of cyclic sulfoximines (3), the behavior of fragment-like reaction products 3 was evaluated in selected in vitro assays (aqueous solubility, metabolic stability, Caco2 permeability, logD) and compared to acyclic analogues (2). In order to overcome the limitations of analyzing such small and fragment-like compounds we also compared the in vitro properties of..."

Preclinical

Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma. (PubMed, Cell Rep) - "Small-molecule inhibition of SEC using clinically relevant CDK9 inhibitors restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a rationale for further exploration of SEC inhibition as a promising therapeutic approach to this intractable disease."

Journal

Current and emerging therapies for patients with acute myeloid leukemia: a focus on MCL-1 and the CDK9 pathway. (PubMed, Am J Manag Care) - "The CDK9 inhibitors alvocidib, atuveciclib, and TG02 have completed phase 1/2 clinical trials, with results available for the alvocidib trial showing improved complete remission rates (70% vs 46%; P = .003) for alvocidib in combination with cytarabine and mitoxantrone, versus cytarabine/daunorubicin, in patients with newly diagnosed AML. A phase 1b study is also ongoing to investigate alvocidib in combination with B-cell lymphoma-2 inhibitor venetoclax for R/R AML. Although further research is needed, CDK9 inhibitors represent a promising new approach for the treatment of AML."

Clinical • Journal

Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=80; Completed; Sponsor: Bayer; Active, not recruiting ➔ Completed

Clinical • Trial completion

Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=80; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting; N=184 ➔ 80; Trial primary completion date: Feb 2017 ➔ Aug 2016

Clinical • Enrollment change • Enrollment closed • Trial primary completion date

Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=184; Recruiting; Sponsor: Bayer; N=280 ➔ 184

Clinical • Enrollment change

Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=280; Recruiting; Sponsor: Bayer; N=146 ➔ 280; Trial primary completion date: Jun 2016 ➔ Feb 2017

Clinical • Enrollment change • Trial primary completion date

Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=122; Recruiting; Sponsor: Bayer; Trial primary completion date: Sep 2015 ➔ Jul 2016

Clinical • Trial primary completion date