Methylthioadenosine Phosphorylase and AdoMet Synthetase in Cancer

癌症中的甲硫腺苷磷酸化酶和 AdoMet 合成酶

• 批准号: 9052718
• 负责人: Vern L. Schramm
• 金额: $ 29.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052718
• 关键词: Adverse effects; Affinity; Animal Model; Antibodies; Antineoplastic Agents; Back; Biochemical; Biology; Blood; Breast; Cancer Cell Growth; Cancer cell line; Catalysis; Catalytic Domain; Cells; Chemicals; Chromatin; Colon; Complement; Complex; Dose; Drug Combinations; Enzymes; Epitopes; Event; Exhibits; Extrahepatic; Fostering; Gene Expression; Generations; Genes; Goals; Growth; Head and Neck Cancer; Health; Human; Human Genome; Isoenzymes; Isotopes; Kinetics; Knowledge; Ligands; Ligase; Liver; Lung; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolism; Modification; Mus; Natural regeneration; Normal Cell; Pathway interactions; Phenotype; Phosphorylases; Polyamines; Post-Translational Protein Processing; Property; Prostate; Protein Isoforms; Proteins; Recycling; Regulation; Reporting; Research; Resistance; S-Adenosylmethionine; Safety; Specificity; Spermine; Structure; Sulfur; System; Testing; Tissues; Toxic effect; Tumor Tissue; Work; Xenograft procedure; analog; anticancer activity; cancer therapy; design; dimer; feeding; genome analysis; inhibitor/antagonist; innovation; interest; meetings; novel; novel anticancer drug; overexpression; prevent; protein expression; protein protein interaction; quantum; theories; tool; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): A goal of cancer therapy is to stop growth of tumors with minimal effects on normal cells. Transition state theory is being used to design powerful inhibitors for specific enzymes. A transition state analogue (MTDIA) of human 5'-methylthioadenosine phosphorylase (MTAP) inhibits growth of human lung, breast, prostate, colon and head and neck cancers in mouse xenografts. The inhibitor is orally available and shows no toxicity against mice far in excess of effective doses. The inhibitor causes an increase in the normal human metabolite 5'- methylthioadenosine (MTA) in mouse blood, tissues and tumors. Inhibition of MTAP prevents MTA recycling to S-adenosylmethionine (AdoMet). Human FaDu head and neck cancer cell lines made resistant to MTDIA show specific amplification of the MAT2A region, the gene encoding MAT IIa, the catalytic subunit of the cancer- specific AdoMet synthetase. Goals of this research are to investigate the biochemical mechanism of action of MTDIA anticancer effects at the MTAP-MAT IIa interface. MAT IIa is implicated as an anticancer target. The MAT IIa transition state structure will be established to foster design of transition state analogues in this novel anticancer pathway. Similar studies with the MAT I/III isozymes will explore transition state specificity. Hypotheses for the MTDIA mechanism of action include: 1) MTAP inhibition causes metabolic accumulation of MTA; 2) MTA inhibits MAT IIa to deplete AdoMet and cause downstream changes detrimental to tumor growth; 3) MTA or MTDIA disrupt MAT IIa interactions with chromatin-related proteins; 3) MTDIA or MTA alter the expression of MAT IIa or MAT IIb, its regulatory subunit to alter activity or corepressor function, or that 4) MTA and/or MTDIA alter gene expression by interaction with transcription factors. The changes induced by MTDIA treatment are of interest as they cause growth arrest of tumors with a wide margin of safety for host tissues. Transition state analysis of MAT activity will provide a blueprint for inhibitor design of AdoMet metabolism as an anti-cancer target. MTAP and MAT IIa are new, evolving targets for anti-cancer agents. The mechanism of anticancer action for MTDIA will be tested by its effects on MAT IIa/b expression and affinity probing for MTA, MAT and MTDIA interacting factors. The low toxicity and unique mechanism of action of the transition state analogue makes it a promising candidate for multi-drug combinations in cancer therapy.

描述（由申请人提供）：癌症治疗的目标是停止对正常细胞影响最小的肿瘤的生长。过渡状态理论用于设计特定酶的强大抑制剂。人类5'-甲基腺苷磷酸化酶（MTAP）的过渡状态类似物（MTDIA）抑制了小鼠异种移植物中人类肺，乳房，前列腺，结肠和头颈癌的生长。抑制剂可供使用，对小鼠的毒性不超过有效剂量。抑制剂在小鼠血液，组织和肿瘤中导致正常的人类代谢产物5'-甲基噻吩并腺苷（MTA）的增加。 MTAP的抑制可防止MTA回收到S-腺苷甲氨酸（ADOMET）。对MTDIA具有抗性的人类Fadu头和颈癌细胞系显示了MAT2A区域的特异性扩增，即编码MAT IIA的基因，癌 - 特异性ADOMEM合成酶的催化亚基。这项研究的目标是研究MTAP-MAT IIA界面上MTDIA抗癌作用作用的生化机制。 MAT IIA被认为是抗癌目标。将建立MAT IIA过渡状态结构，以促进这种新型抗癌途径中的过渡状态类似物的设计。使用MAT I/III同工酶的类似研究将探索过渡状态的特异性。 MTDIA作用机理的假设包括：1）MTAP抑制作用导致MTA代谢积累； 2）MTA抑制MAT IIA耗尽ADOMET并导致下游变化对肿瘤生长有害； 3）MTA或MTDIA与染色质相关蛋白的MAT IIA相互作用； 3）MTDIA或MTA改变MAT IIA或MAT IIB的表达，其调节子单元更改活动或核心压力函数， 或者4）MTA和/或MTDIA通过与转录因子的相互作用而改变基因表达。 MTDIA治疗引起的变化引起了人们的关注，因为它们会导致肿瘤的生长停滞，并具有很大的安全性宿主组织安全性。 MAT活性的过渡状态分析将为ADOMET替换为抗癌靶标的抑制剂设计提供蓝图。 MTAP和MAT IIA是抗癌药物的新目标。 MTDIA的抗癌作用机制将通过其对MTA，MAT和MTDIA相互作用因子的MAT IIA/B表达和亲和力探测的影响来测试。过渡状态类似物的低毒性和独特的作用机理使其成为癌症治疗中多药组合的有前途的候选人。