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

Announcement
Written By Lani Nguyen

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

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. BPS Bioscience BRD4 (BD1 + BD2) TR-FRET Assay Kit, BPS Catalog #32612) (https://bpsbioscience.com/brd4-bd1-bd2-tr-fret-assay-kit-32612)

  12. 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)

  13. 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.

  14. Cancer Stat Facts: Thyroid Cancer, https://seer.cancer.gov/statfacts/html/thyro.html

  15. 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.

  16. 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.

  17. 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

  18. 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.

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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

Lani Nguyen
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