AU-18069 / Orion Corp, Dr. Reddy’s - LARVOL DELTA

Evaluation of AU-18069, a novel small molecule CBP/p300 bromodomain inhibitor for the treatment of cancers (AACR 2022) - "Lead candidate AU-18069 demonstrated that selective CBP/p300 bromodomain inhibitors are efficacious in models of hematologic malignancies and solid cancers in vitro and in vivo. Further evaluation of efficacy in other xenograft models, as a single agent as well as in combination with other agents is planned. Long term toxicological and safety pharmacology evaluation in different species and other IND enabling studies are in progress to support progression of this compound to clinical trials."

Breast Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Prostate Cancer • Solid Tumor • AR • BRCA • BRCA1 • CREBBP • HIF1A • MYC

[VIRTUAL] Evaluation of AU-18069, a novel small molecule CBP/p300 bromodomain inhibitor for the treatment of cancers (AACR 2021) - "Multiple potent and selective CBP/p300 BRD inhibitors that are structurally unrelated to known inhibitors have been identified by iterative medicinal chemistry and SAR based approaches. The lead compound, AU-18069 was optimized towards attaining good potency, physicochemical properties and DMPK profile. AU-18069 potently inhibited viability and proliferation of a wide range of cell lines derived from prostate cancer, CBP mutant and MYC-dependent hematological cancers and demonstrated improved PK profile in rodent models in comparison with a compound, currently in clinical trials."

Genito-urinary Cancer • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor • AR • BRCA • BRCA1 • CD4 • CREBBP • HIF1A • MYC

Therapeutic targeting of estrogen receptor positive breast cancer with the BET bromodomain inhibitor ODM-207 (AACR 2018) - "The purpose of this study was to determine the anticancer activity of the novel BET bromodomain inhibitor ODM-207 in pre-clinical ER+ breast cancer models, and further, to look for cancer-associated signaling pathways suppressed by BET inhibitors.Methodology and ODM-207 is a novel, highly selective BET bromodomain inhibitor structurally distinct from JQ1 and its benzodiazepine-related derivatives. Our results indicate that the novel BET bromodomain inhibitor ODM-207, which is currently in Phase I clinical trials for treating solid tumors, causes significant growth inhibition and cell cycle arrest in pre-clinical models of ER+ breast cancer, and regulates multiple crucial signaling pathways involved in breast cancer cell cycle and survival."

Hormone Receptor Breast Cancer

Identification of SMARCA2/4 degraders for the treatment of SMARCA4-mutant and other cancers (AACR 2018) - "...SMARCA2 (BRM) and SMARCA4 (BRG1), contain a bromodomain and an ATPase domain...Functional analysis of these compounds in a panel of cell lines indicated that the degradation of SMARCA2 or SMARCA2/4 resulted in potent anti-proliferative activity in selected cell lines that was not strictly dependent upon SMARCA4 status. Additionally, these compounds displayed reasonable drug-like properties including solubility, metabolic stability and pharmacokinetics in mice supporting their potential to fully evaluate the impact of SMARCA2/4 degradation and to develop them as a novel therapeutic approach."

Oncology

[VIRTUAL] Targeting cancer with selective cbp/p300 bromodomain inhibitors (AACR-II 2020) - "In summary, our studies demonstrate that selective CBP/p300 bromodomain inhibitors are potent in models of hematologic malignancies and solid tumors in-vitro. Profiling of efficacy in xenograft models, and further toxicological evaluation are in progress."

Genito-urinary Cancer • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor • AR • BIRC5 • BRCA • BRCA1 • EP300 • HIF1A • MYC • TCF7L2

[VIRTUAL] First in class orally bioavailable BETBRD degraders (AACR-II 2020) - "Background: Inhibition of Bromodomain and extra-terminal (BET) family proteins by small molecules is actively being pursued as a therapeutic strategy in the clinics... Potent and selective BET protein degraders were identified by conjugating novel BET BRD ligands with both VHL and CRBN ligands. Optimization of these first generation BET degraders led to improved metabolic stability, translating into low iv clearance in rodents. Further evaluation of these compounds as prodrugs resulted in good oral exposures."

Oncology • Solid Tumor • CRBN

Antitumor activity of ODM-207, a novel BET bromodomain inhibitor, in nonclinical models of ER+ breast cancer as single agent and as a combination treatment (AACR 2019) - "For gene expression analyses, breast cancer cells were treated with ODM-207 or reference BET inhibitor JQ1 and differentially expressed genes were analyzed by RNA-sequencing. In summary, ODM-207, which is currently in Phase I clinical trials for treating solid tumors, causes significant growth inhibition in pre-clinical models of ER+ breast cancer and enhances antiproliferative activity of palbociclib, providing a rationale for development of a combination therapy."

Anti-tumor efficacy of SMARCA degraders in pre-clinical models of cancer (AACR 2019) - "Although genetic silencing of SMARCA2 leads to potent anti-proliferative activity in SMARCA4-deficient cancer cell lines, pharmacological studies with a probe capable of binding to SMARCA2 and SMARCA4 bromodomain have failed to show such an anti-proliferative phenotype. Observed efficacy was correlated with the target degradation in the tumor supporting the potential to further develop them for cancer therapy. Based on the reported vulnerability of SMARCA4-deficient cell lines of diverse tumor origin to agents targeting PARP, PI3K/AKT and EZH2, combination effects with SMARC2 degrader are being interrogated."

PARP Biomarker