DISCOVERY OF FIRST-IN-CLASS NSD2 DEGRADERS FOR CANCER THERAPY

发现用于癌症治疗的一流 NSD2 降解剂

• 批准号: 10670764
• 负责人: Lindsey Ingerman James
• 金额: $ 32.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-23 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670764
• 关键词: Acute Lymphocytic Leukemia; Affinity; Binding; Biological Assay; Biology; Cancer Biology; Cancer cell line; Cell Line; Cells; Cellular Assay; Chemicals; Childhood Acute Lymphocytic Leukemia; Chromosomes; Complex; Data; Development; Drug Targeting; Epigenetic Process; Family; Gene Silencing; Genes; Genetic; Genetic Transcription; Goals; Hand; Hematopoietic Neoplasms; Histones; In Vitro; Knowledge; Lead; Length; Ligands; Lysine; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Multiple Myeloma; Mutate; Mutation; N-terminal; Nuclear Receptors; Oncogenic; Oncology; Oncoproteins; PHD Finger; PWWP Domain; Pathogenesis; Patients; Permeability; Pharmaceutical Chemistry; Pharmacology; Phenocopy; Play; Proteins; Qualifying; Reader; Reagent; Recurrence; Reporting; SET Domain; Sampling; Structure; Technology; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Agents; Work; acute lymphoblastic leukemia cell; cancer genome; cancer subtypes; cancer therapy; design; drug discovery; epigenetic regulation; epigenetic therapy; epigenome; gain of function mutation; improved; inhibitor; insight; knock-down; member; meter; novel; overexpression; pre-clinical; pre-clinical assessment; prevent; protein degradation; receptor; receptor binding; recruit; screening; small molecule; small molecule inhibitor; therapeutic target; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

ABSTRACT Epigenetic dysregulation is an emerging hallmark of cancers, and examples of cancer associated overexpression, mutation, translocation, or aberrant recruitment of the proteins which regulate the epigenome are rapidly emerging. NSD2 (nuclear receptor-binding SET domain-containing 2) is a key player in epigenetic regulation, known for its ability to mono- and dimethylate lysine 36 of histone 3 (H3K36). This mark is associated with active transcription, and elevated levels of H3K36me2 lead to aberrant activation of normally silenced genes. Consequently, NSD2 is a potent oncoprotein and has been implicated as a therapeutic target for a variety of cancers. NSD2 was found to be among the most frequently mutated genes across 1,000 pediatric cancer genomes representing 21 different pediatric cancer subtypes. A study in pediatric acute lymphoblastic leukemia (ALL) cell lines and patient samples revealed a recurring gain of function mutation (E1099K) which resulted in elevated H3K36me2 levels. Furthermore, NSD2 is involved in the pathogenesis of multiple myeloma (MM) which is the second most common blood cancer. 15-20% of MM patients carry a translocation between chromosomes 4 and 14 [t(4;14)(p16.3;q32)] of which NSD2 is thought to be the primary oncogenic driver. In addition to its catalytic SET domain, NSD2 contains several methyl-lysine (Kme) reader domains including four PHD fingers and two PWWP domains which are thought to be critical in propagating H3K36me2 and recruiting NSD2 to its oncogenic target genes. Although NSD2 clearly shows promise as a therapeutic target in oncology, no small molecule ligands have been reported to date and it remains unclear as to which domains are `druggable' and function most critically in promoting tumorigenesis. The creation of high-quality NSD2 chemical probes will clearly provide much needed insight and serve as critical reagents in assessing preclinical target validity, while providing the potential for an immediate transition to a drug discovery effort. Our recent efforts to target the N-terminal PWWP domain of NSD2 have been successful in producing potent lead compounds. With novel NSD2 inhibitors in hand, we aim to explore the development of NSD2 protein degradation reagents which capitalize on advantages of small molecule inhibitors while moving beyond the limitations of traditional receptor pharmacology. This emerging drug discovery strategy is particularly well-suited for NSD2 because 1) it is a large multi-domain protein and we lack knowledge of the best domain to target, 2) inhibition of a single domain may not be sufficient to phenocopy NDS2 genetic knockdown results and more broadly prevent tumorigenesis, and 3) Kme reader domains are generally viewed as difficult drug targets. The overall objective of this proposal is to apply medicinal chemistry, chemical biology, and cancer biology approaches to discover first-in-class NSD2 bifunctional degraders in order to better understand NSD2 cancer biology, to assess NSD2 preclinical target validity, and as potential therapeutic agents.

摘要 表观遗传失调是癌症的一个新的标志， 调节表观基因组的蛋白质的过表达、突变、易位或异常募集 正在迅速崛起。NSD 2（nuclear receptor-binding SET domain containing 2，核受体结合SET结构域2）是表观遗传学中的关键参与者。 调节，以其单-和二甲基化组蛋白3的赖氨酸36（H3 K36）的能力而闻名。这个标记与 H3 K36 me 2的水平升高导致正常沉默基因的异常激活。 因此，NSD 2是一种有效的癌蛋白，并且已经被认为是多种肿瘤的治疗靶点。 癌的NSD 2被发现是1,000个儿科癌症中最常见的突变基因之一。 代表21种不同儿科癌症亚型的基因组。小儿急性淋巴细胞白血病的临床研究 (ALL)细胞系和患者样品揭示了功能突变（E1099 K）的反复获得，其导致 H3 K36 me 2水平升高。此外，NSD 2参与多发性骨髓瘤（MM）的发病机制， 是第二常见的血癌。15-20%的MM患者携带染色体间易位 4和14 [t（4;14）（p16.3;q32）]，其中NSD 2被认为是主要的致癌驱动因子。 除了其催化SET结构域之外，NSD 2还含有几个甲基赖氨酸（Kme）阅读器结构域，包括 四个PHD指和两个PWWP结构域，其被认为在传播H3 K36 me 2中是关键的， 将NSD 2募集到其致癌靶基因中。尽管NSD 2清楚地显示出作为治疗靶点的希望， 在肿瘤学中，迄今为止还没有报道过小分子配体，并且仍然不清楚哪些结构域是 “可药用”，在促进肿瘤发生方面发挥着最关键的作用。高品质NSD 2化学品的创造 探针将清楚地提供急需的洞察力，并作为评估临床前靶点的关键试剂 有效性，同时提供立即过渡到药物发现工作的潜力。我们最近的努力， 靶向NSD 2的N-末端PWWP结构域的方法已经成功地产生了有效的先导化合物。 随着新型NSD 2抑制剂的出现，我们的目标是探索NSD 2蛋白降解试剂的开发 其利用了小分子抑制剂的优点，同时超越了传统的 受体药理学这种新兴的药物发现策略特别适合NSD 2，因为1）它 是一个大的多结构域蛋白质，我们缺乏最好的结构域的知识，以目标，2）抑制单一的 结构域可能不足以表型复制NDS 2基因敲低结果， 3）Kme阅读器结构域通常被视为困难的药物靶标。总体目标 该提案的一个重要目的是应用药物化学，化学生物学和癌症生物学方法来发现 一流的NSD 2双功能降解剂，以更好地了解NSD 2癌症生物学，评估NSD 2 临床前靶向有效性和作为潜在的治疗剂。

项目成果

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2.

• DOI: 10.1021/acs.jmedchem.0c01768
• 发表时间: 2021-02-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Ferreira de Freitas R;Liu Y;Szewczyk MM;Mehta N;Li F;McLeod D;Zepeda-Velázquez C;Dilworth D;Hanley RP;Gibson E;Brown PJ;Al-Awar R;James LI;Arrowsmith CH;Barsyte-Lovejoy D;Min J;Vedadi M;Schapira M;Allali-Hassani A
• 通讯作者: Allali-Hassani A