CDK4/6 inhibitors have shown clinical benefits in hormone receptor positive breast cancer. However, monotonous indications and unclear resistance mechanisms greatly limit the clinical application of these inhibitors. We attempt to improve the therapeutic effect of CDK4/6 inhibitors against breast cancer by combination with BET inhibitors. Although this combination therapy has begun to be studied in recent clinical trials, the mechanism of action is not clear. We provide the evidence that CDK4/6 inhibitor LY2835219 plus BRD4 inhibitor OTX-015 synergistically inhibits both ER positive and triple-negative breast cancer cells growth in vitro and in vivo. Mechanistically, LY2835219 accelerates the degradation of BRD4 through the proteasome pathway via inhibition of CDK4 activity. This instability of BRD4 protein in turn enhances the anti-tumor effect of CDK4/6 inhibitor by suppressing transcription of DNA damage repair gene RAD51, and synergistically promotes γ-H2AX accumulation and DNA double-strand breaks. Overall, we demonstrated the potential combined therapeutic value of CDK4/6 and BRD4 inhibitors and elucidated the mechanisms, which may provide a new rational approach for breast cancer patients.

2025-01-01·ANTI-CANCER DRUGS

EP-0108A is a moderation selectively BRD4 BD2 inhibitor with potential AML tumor suppression

Article

作者: Li, Li ; Liu, Shuang ; Zhu, Hui

Acute myeloid leukemia is the most common type of acute leukemia in adults. The epigenetic molecule BRD4 is a member of the bromodomain and extra-terminal family and plays an important role in the occurrence and development of tumors. BRD4 is essential for oncogene expression, including c-Myc. So, BRD4 inhibition is considered as an effective strategy for the treatment of hematological and solid malignancies. In recent years, several small molecule inhibitors targeting BRD4 have been developed. However, these inhibitors had excessive hematological toxicity due to the lack of specific binding to BD1 and BD2 domains of BRD4, while other inhibitors with high selectivity lose their antitumor efficacy. To balance the relationship between efficacy and safety, we developed EP-0108A, a BRD4 inhibitor with moderate selectivity for the BD2 domain over BD1 domain of BRD4. Our results show that EP-0108A has antitumor effects in MV4-11 and Kasumi-1 cell line-derived xenograft mouse models without significant effects on heart or breathing safe in rats and Beagle dogs. In repeated dose toxicity studies, EP-0108A showed reversible hematological and gastrointestinal toxicity in both rats and dogs. Our findings indicate that EP-0108A has the potential to be a new therapeutic agent for the treatment of cancer.

2024-12-12·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Dual CDK6/BRD4 Inhibitor Inducing Apoptosis and Increasing the Sensitivity of Ferroptosis in Triple-Negative Breast Cancer

Article

作者: Li, Shang ; Ma, Liangliang ; Zheng, Long ; Luo, Zhongwen ; Zhang, Yonglei ; Kong, Lingyi ; Jiang, Yuhan ; Yin, Fucheng ; Wang, Xiaobing

Bromodomain-containing protein 4 (BRD4) is the most promising target for the treatment of triple-negative breast cancer (TNBC). However, its inherent resistant and acquired drug resistance limits its potential clinical application. Recently it has been shown that cyclin-dependent kinases 4/6 (CDK4/6) inhibitors can reincrease the sensitivity of TNBC cells to BRD4 inhibitors by combination therapy, so we designed a series of dual target CDK6/BRD4 inhibitors. Among the newly synthesized compounds, BC13 exhibited potent inhibitory activity against CDK6 and BRD4. It also displayed potent antiproliferative activity against TNBC cells. In vivo experiments showed that BC13 has potent antitumor activity in the MDA-MB-231 xenograft mouse model, without observable side effects. BC13 demonstrates profound synergistic antitumor effects with ferroptosis inducer in TNBC cells. Therefore, BC13 is a novel dual inhibitor of CDK6/BRD4 for the treatment of TNBC either as a single agent or in combination with RSL3.

项与 BRD4 inhibitor (Kainos Medicine, Inc.) 相关的新闻（医药）

2023-06-05

·modelmedicines.com

Model Medicines Announces Nomination of Preclinical Candidate, MDL-4101, Targeting BRD4 for the Treatment of Thyroid Cancer

Proprietary GALILEO™ AI drug discovery platform models undruggable oncology target BRD4 and discovers MDL-4101 as a potent and selective inhibitor BRD4 is a validated oncology target across multiple cancers, but has been considered difficult, or potentially undruggable, due to challenges related to specificity and toxicity [1] [2] BRD4 is significantly upregulated in aggressive thyroid cancers with high unmet medical need, driving tumor progression and metastasis through aberrant activation of oncogenic proteins [3] MDL-4101 demonstrates BRD4 binding in cell-free assay and robust anti-tumor activity in a preclinical model of aggressive human thyroid cancer (CGTH-W-1), suppressing cell proliferation and metastatic capacity IND-enabling studies planned for MDL-4101 to address the significant unmet need for new targeted therapies in thyroid cancers LA JOLLA, CA — Model Medicines, a leading human health company specializing in generative AI-driven drug discovery, today announced the nomination of preclinical candidate MDL-4101, a novel-acting small molecule inhibitor of bromodomain-containing protein 4 (BRD4), for the treatment of thyroid and other cancers. MDL-4101 demonstrates the company's commitment to leveraging AI to discover novel therapies for aggressive cancers with high unmet medical needs. In particular, MDL-4101 was discovered and the BRD4 program [4] was launched to overcome the limitations of previous BRD4 therapeutics, which have failed to reach the pharmacy [5]. The nomination of MDL-4101 resulted from Model Medicines' proprietary AI-driven drug discovery platform, GALILEO™, modeling the epigenetic oncology target BRD4, a promising but difficult therapeutic target. BRD4, a member of the bromodomain and extra-terminal (BET) protein family, has emerged as a highly validated therapeutic target across a wide range of cancers. As a key regulator of oncogene expression, BRD4 has been shown to drive tumorigenesis in multiple solid and hematologic malignancies, including breast cancer, prostate cancer, leukemias, and lymphomas. Despite this broad potential, BRD4 has proven challenging to drug selectively, leading to safety and tolerability issues, and has been labeled as difficult to drug, or undruggable, due to the inability of conventional approaches to yield selective and tolerable inhibitors. To date, no selective BRD4 inhibitor has received regulatory approval, underscoring the urgent need for new modalities to effectively target this high-value protein [6-10]. Model Medicines deployed its proprietary GALILEO™ platform to discover and design MDL-4101 as a selective BRD4 inhibitor that could overcome the limitations of previous programs. By leveraging machine learning to explore vast chemical space and predict drug-like properties, Model Medicines successfully identified MDL-4101 as a potent, selective, and orally bioavailable BRD4 inhibitor, succeeding where traditional approaches have struggled. MDL-4101 demonstrates BRD4 binding in cell free assay [11] and robust anti-tumor activity in a preclinical model of thyroid cancer (CGTH-W-1)[12], suppressing cell proliferation and metastatic capacity. Additionally, preclinical studies have shown evidence of activity in human glioblastoma, prostate, and testicular cancers. "The successful nomination of MDL-4101 as our first preclinical oncology candidate is a significant milestone for Model Medicines and underscores the unparalleled ability of our AI platform to solve previously intractable challenges in drug discovery," said Daniel Haders, Ph.D., CEO and founder of Model Medicines. "BRD4 is a target that has long captivated drug hunters due to its central role in cancer, but has evaded their grasp. By leveraging AI to intelligently discover and design compounds with optimal properties, we discovered a molecule in MDL-4101 that potentially unlocks the full potential of BRD4 inhibition. We believe this is just the beginning of what our AI-powered approach can achieve against undruggable targets in oncology and beyond." Thyroid cancer is the most common endocrine malignancy and the tenth most common cancer in the world, accounting for an estimated 586,000 cases worldwide in 2020 [13]. Thyroid cancer is also the fifth most common cancer type in the US, with 44,000 cases in 2022 [13, 14]. BRD4 is found to be up-regulated across many human thyroid cancers and cancer models [15]. The most common subtypes include the differentiated thyroid cancers papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), which have good prognosis with early intervention [16]. However, treatment options for more aggressive forms, such as anaplastic thyroid carcinoma (ATC) and subtypes such as squamous cell carcinoma of the thyroid (SCCT), remain limited and challenging. Today’s reported results evaluated MDL-4101 in a BRD4-enriched human thyroid cancer model (CGTH-W-1) that was derived from a sample of metastatic SCCT, which has a five-year survival rate of only 6.4% [17]. SCCT is a very aggressive tumor with a poor prognosis. The most recommended treatment involves surgical resection with adjuvant radiotherapy and chemotherapy despite its poor reported outcomes [18]. Thus, there is a high unmet medical need for novel therapeutic interventions. "The preclinical data for MDL-4101 in human thyroid cancer is highly encouraging and speaks to the immense promise of a selectivBRD4 inhibitor," said Dr. Launa Aspeslet, Senior Scientific & Clinical Advisor to Model Medicines. "By unleashing the untapped potential of BRD4 inhibition, we believe MDL-4101 could represent a transformative advance for patients with thyroid and other BRD4 related cancers who currently face a paucity of effective treatment options. We are excited to rapidly progress MDL-4101 into first-in-human studies, while exploring its potential in other cancers driven by BRD4." Model Medicines plans to initiate Investigational New Drug (IND) enabling studies for MDL-4101, with the goal of submitting an IND application to the U.S. Food and Drug Administration (FDA) and initiating a Phase 1 clinical trial in patients in the near future. Preprint Papers: In a recent preprint paper titled ChemPrint: An AI-Driven Framework for Enhanced Drug Discovery, Model Medicines describes their drug discovery approach to two undruggable oncology targets, AXL and BRD4, and reports on the compound library that yielded MDL-4101. About Model Medicines Model Medicines is a generative AI-driven human health company that uses AI to model all of chemistry and human biology to accelerate the creation of life-changing drugs. The company was founded in 2019 to deliver on the promise of AI drug discovery. With more than 192 compounds for 26 targets, they are delivering on the promise of AI drug discovery. The company has developed a robust pipeline of patent-pending therapeutics for oncology, infectious diseases, gastric disorders, neurological disorders, and weight disorders. The company is based in La Jolla, CA. To learn more, visit www.modelmedicines.com References To KKW, Xing E, Larue RC, Li PK. BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications. Molecules. 2023 Mar 29;28(7):3043. doi: 10.3390/molecules28073043. PMID: 37049806; PMCID: PMC10096006. Liang, D., Yu, Y., & Ma, Z. (2020). Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery. In European Journal of Medicinal Chemistry (Vol. 200, p. 112426). Elsevier BV. https://doi.org/10.1016/j.ejmech.2020.112426 Gao X, Wu X, Zhang X, Hua W, Zhang Y, Maimaiti Y, Gao Z, Zhang Y. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer. Biochem Biophys Res Commun. 2016 Jan 15;469(3):679-85. doi: 10.1016/j.bbrc.2015.12.008. Epub 2015 Dec 18. PMID: 26707881. Umansky, T., Ramesh, N., Woods, V., Russell, S. M., Smith, D., & Haders, D. (2024). ChemPrint: An AI-Driven Framework for Enhanced Drug Discovery. https://doi.org/10.1101/2024.03.22.586314 Sun, Y., Han, J., Wang, Z., Li, X., Sun, Y., Hu, Z. Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitors for the Treatment of Hematological Malignancies and Solid Tumors: A Systematic Study of Clinical Trials. Front. Pharmacol., 25 January 2021 Sec. Pharmacology of Anti-Cancer Drugs, Volume 11 - 2020, https://doi.org/10.3389/fphar.2020.621093 Hu, J., Pan, D., Li, G. et al. Regulation of programmed cell death by Brd4. Cell Death Dis 13, 1059 (2022). https://doi.org/10.1038/s41419-022-05505-1 Shafran JS, Jafari N, Casey AN, Győrffy B, Denis GV. BRD4 regulates key transcription factors that drive epithelial-mesenchymal transition in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2021 Mar;24(1):268-277. doi: 10.1038/s41391-020-0246-y. Epub 2020 Jul 21. PMID: 32690869; PMCID: PMC7855805. Tsukamoto T, Nakahata S, Sato R, Kanai A, Nakano M, Chinen Y, Maegawa-Matsui S, Matsumura-Kimoto Y, Takimoto-Shimomura T, Mizuno Y, Kuwahara-Ota S, Kawaji Y, Taniwaki M, Inaba T, Tashiro K, Morishita K, Kuroda J. BRD4-Regulated Molecular Targets in Mantle Cell Lymphoma: Insights into Targeted Therapeutic Approach. Cancer Genomics Proteomics. 2020 Jan-Feb;17(1):77-89. doi: 10.21873/cgp.20169. PMID: 31882553; PMCID: PMC6937128. Wang, ZQ., Zhang, ZC., Wu, YY. et al. Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy. Sig Transduct Target Ther 8, 420 (2023). https://doi.org/10.1038/s41392-023-01647-6 Coleman, D.J., Gao, L., Schwartzman, J. et al. Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer. Sci Rep 9, 3823 (2019). https://doi.org/10.1038/s41598-019-40518-5 BPS Bioscience BRD4 (BD1 + BD2) TR-FRET Assay Kit, BPS Catalog #32612) (https://bpsbioscience.com/brd4-bd1-bd2-tr-fret-assay-kit-32612) Eurofins OncoPanel® Proliferation Assay in CGTH-W-1 Cells, 5-day Singleplex High Content Imaging (https://www.eurofinsdiscovery.com/catalog/oncopanel%c2%ae-proliferation-assay-in-cgth-w-1-cells-5-day-singleplex-high-content-imaging/CGTSP05) Shank JB, Are C, Wenos CD. Thyroid Cancer: Global Burden and Trends. Indian J Surg Oncol. 2022 Mar;13(1):40-45. doi: 10.1007/s13193-021-01429-y. Epub 2021 Sep 4. PMID: 35462648; PMCID: PMC8986939. Cancer Stat Facts: Thyroid Cancer, https://seer.cancer.gov/statfacts/html/thyro.html Gao X, Wu X, Zhang X, Hua W, Zhang Y, Maimaiti Y, Gao Z, Zhang Y. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer. Biochem Biophys Res Commun. 2016 Jan 15;469(3):679-85. doi: 10.1016/j.bbrc.2015.12.008. Epub 2015 Dec 18. PMID: 26707881. Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013 Mar 23;381(9871):1058-69. doi: 10.1016/S0140-6736(13)60109-9. Epub 2013 Mar 22. PMID: 23668556; PMCID: PMC3931461. Ding, W., Gao, X., & Ran, X. (2024). Progress in diagnosing and treating thyroid squamous cell carcinoma under the 5th edition of WHO classification. In Frontiers in Endocrinology (Vol. 14). Frontiers Media SA. https://doi.org/10.3389/fendo.2023.1273472 Struller F, Senne M, Falch C, Kirschniak A, Konigsrainer A, Muller S. Primary squamous cell carcinoma of the thyroid: Case report and systematic review of the literature. Int J Surg Case Rep. 2017;37:36-40. doi: 10.1016/j.ijscr.2017.06.011. Epub 2017 Jun 13. PMID: 28633125; PMCID: PMC5479948. Model Medicines is a generative AI-driven human health company that uses AI to model all of chemistry and human biology to accelerate the creation of life-changing drugs. The company was founded in 2019 to deliver on the promise of AI drug discovery. With more than 192 compounds for 26 targets, they are delivering on the promise of AI drug discovery. The company has developed a robust pipeline of patent-pending therapeutics for oncology, infectious diseases, gastric disorders, neurological disorders, and weight disorders. The company is based in La Jolla, CA. To learn more, visit www.modelmedicines.com

临床1期

2022-08-01

·PRNewswire

BridGene Biosciences names David Sperandio, Ph.D., as Head of Chemistry

SAN JOSE, Calif., Aug. 1, 2022 /PRNewswire/ -- BridGene Biosciences, Inc., a biotechnology company using a proprietary chemoproteomics technology to discover and develop small molecules for high value, traditionally undruggable targets, today announced that David Sperandio, Ph.D., a medicinal chemist with more than 20 years' experience, has joined the company as the Head of Chemistry. Dr. Sperandio, an inventor on 23 patents and author of 25 peer-reviewed publications, has extensive experience leading cross-functional teams from molecule discovery through IND filing. Dr. Sperandio will lead the BridGene chemistry team and supervise research into covalent chemistry, chemical proteomics and quantitative mass spectrometry as methods for identifying undruggable targets. Additionally, Dr. Sperandio will be responsible for advancing BridGene's internal pipeline of first-in-class drugs for hard-to-drug targets in oncology. BridGene co-founder and CEO Ping Cao, Ph.D., commented, "David's addition to our leadership team and the recent Series B financing deepen BridGene's capabilities for using IMTAC™ to discover new drugs for novel and traditionally undruggable targets. David's leadership and experience will help expand BridGene's library of molecules to identify as potential drug candidates as we aim to advance a pipeline of first-in-class drugs for these new targets." Dr. Sperandio most recently served as an Executive Director at Biomea Fusion, where he led the team that identified BMF-500, a potential best-in-class targeted covalent FLT-3 inhibitor for the treatment of acute myeloid leukemia. Prior to joining Biomea Fusion, Sperandio led a collaboration of R2M Pharma Inc. with Tenaya Therapeutics Inc., which discovered novel HDAC6 inhibitors for cardiovascular diseases and was key for the clinical development of TN-301, an experimental treatment for heart failure. Dr. Sperandio started his career at Celera Corp. and focused on the structure-guided discovery of covalent reversible serine-protease inhibitors. He later moved to Gilead Sciences Inc., where he led the chemistry team that discovered Alobresib (GS-5829), a novel BRD4 inhibitor for prostate cancer, and Presatorvir (GS-5806), the first small molecule RSV fusion inhibitor that reached the clinic and showed proof of concept in men. Dr. Sperandio commented, "I am excited to join BridGene at such a dynamic time for the company. 2022 has been a remarkable year so far, and I look forward to working closely with the management team to continue to drive the success of IMTAC™." Dr. Sperandio obtained his doctoral degree in Organic Chemistry from the University of Zurich and completed his postdoctoral research at Stanford University. About BridGene Biosciences BridGene is a biotechnology company focused on discovering and developing innovative small molecules that drug traditionally undruggable targets, providing new paths to treat diseases. By using its proprietary chemoproteomics platform, IMTAC™, BridGene can screen small molecules against proteins in live cells to discover drug candidates for high value and traditionally undruggable targets. For this purpose, BridGene takes advantage of its proprietary, diverse library of tagged, drug-like small molecules. The ultimate goal is to enable breakthrough small molecule drug discovery with expanded mechanisms to treat diseases with targets previously inaccessible to small molecules. The uniqueness of BridGene's technology allows it to perform IMTAC™ screening for both covalent and non-covalent molecules, target different amino acids and discover new targets for disease treatments by deconvoluting phenotypic screening hits. The company is advancing a diversified pipeline of first-in-class drugs for targets in multiple disease areas. For more information, visit . Contact Tiberend Strategic Advisors, Inc. Investors Jonathan Nugent +1-205-566-3026 [email protected] Media Bill Borden +1-732-910-1620 [email protected] Dave Schemelia +1-609-468-9325 [email protected] SOURCE BridGene Biosciences

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