DISCOVERY AND DEVELOPMENT OF CANCER THERAPEUTICS FOR NEXT PROGRAM

下一个项目的癌症治疗方法的发现和开发

• 批准号: 10716676
• 负责人: MICHAEL DIFILIPPANTONIO
• 金额: $ 2236.48万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-09-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716676
• 关键词: ATP phosphohydrolase; Animals; Biological; Biological Assay; Biological Products; Budgets; Clinical Trials; Contractor; Development; Dose; Goals; In Vitro; Knowledge; MCL1 gene; MLL gene; Malignant Neoplasms; Mind; Mission; Nature; Outcome; Patients; Performance; Pharmaceutical Chemistry; Pharmacologic Substance; Phase I Clinical Trials; Process; Research Project Grants; Running; Schedule; Series; Specificity; Stream; Synthesis Chemistry; Therapeutic; Time; TimeLine; Validation; anti-cancer therapeutic; clinical candidate; commercialization; drug discovery; experience; flexibility; high throughput screening; in vivo; inhibitor; novel therapeutics; programs; scale up

The mission of NExT is to develop agents that eventually become approved anticancer therapeutics. Numerous interconnected activities need to be successfully completed before an IND can be filed with the FDA to move into clinical trials. As is the case with scientific research projects, drug discovery is often fraught with unforeseen technical difficulties, biological dead ends, and the need to retrace one’s steps along the way. Successfully navigating the drug discovery process requires the ability to quickly take advantage of new knowledge, the flexibility to change technical approach mid-stream, and an understanding that project timelines and budgets can and will deviate at many times along the way. Therefore, although the drug discovery process is often depicted as a linear series of stage gates, in reality projects seldom follow a predictable linear path, but rather entail the performance of numerous, not always sequential, and often iterative, activities, the exact timing of which can rarely be predicted a priori. This has been one of the main, and in fact the hardest, lesson learned from more than a decade of drug discovery in DCTD. DCTD’s mission to advance new therapies into patients requires that promising compounds navigate numerous technical activities in order to qualify for IND directed studies. This process includes the development of a high throughput screening assay, running the high throughput screen (often with >200,000 compounds), validation of hit compounds, development and use of secondary assays assessing the specificity and selectivity of the hit compounds against the target, medicinal and synthetic chemistry, in vitro and in vivo (e.g. animal) dose and schedule, efficacy, PK and PD studies in order to consider a compound sufficiently validated to have the intended biological outcome. The experience of DCTD’s drug discovery efforts, over the past decade has demonstrated that 6 - 10 years is required to go from conducting a high-throughput screen to having a clinical candidate and conducting IND-enabling studies, and that many projects fail at different stages along the way to reaching that goal. Under a previous NS TO (#34), the contractor successfully demonstrated the ability to deliver to NCI at least 1 Clinical Candidate (p97 AAA ATPase inhibitor), were close to nominating a Clinical Candidate for a second project (Mcl-1 inhibitor) when it was terminated by the applicant so they could pursue commercialization with a Pharmaceutical company, and were close to nominating a Clinical Candidate for a third project (WDR5-MLL1 inhibitor) within a 5-year POP. At the conclusion of TO-34 we therefore initiated another NS-TO (20-019) with the same goal in mind to deliver at least 1 Clinical Candidate. Due to the nature of the deliverable, only projects which were further along in the pipeline were considered under the NS TO. For this reason, NCI is submitting this new NS TO to allow for projects at earlier stages in the pipeline that, if successful, would feed into TO20-019. Additionally, this new Task Order would also allow for activities required subsequent to the identification of a Clinical Candidate, such as scale-up and manufacturing to support IND-enabling studies and Phase 1 Clinical Trials, particularly in the case of Biologics.

NExT的使命是开发最终成为批准的抗癌治疗药物的药物。在向FDA提交IND以进入临床试验之前，需要成功完成许多相互关联的活动。与科学研究项目一样，药物发现往往充满了无法预见的技术困难，生物学上的死胡同，以及需要沿着沿着回溯的步骤。 成功地驾驭药物发现过程需要快速利用新知识的能力，中途改变技术方法的灵活性，以及理解项目时间表和预算可以并且将在许多时候偏离沿着。因此，尽管药物发现过程通常被描述为一系列线性的阶段门，但实际上项目很少遵循可预测的线性路径，而是需要执行许多不总是连续的，而且经常是迭代的活动，其确切时间很少可以事先预测。这是从DCTD十多年的药物发现中吸取的主要教训之一，事实上也是最困难的教训。 DCTD的使命是将新疗法推进到患者中，这需要有前景的化合物通过许多技术活动，以便有资格进行IND指导的研究。该过程包括开发高通量筛选测定，运行高通量筛选（通常具有> 200，000种化合物）、验证命中化合物、开发和使用二级测定法评估命中化合物对靶标的特异性和选择性、体外和体内的药物和合成化学（例如，动物）剂量和时间表、功效、PK和PD研究，以考虑经充分验证具有预期生物学结果的化合物。过去十年来，DCTD药物发现工作的经验表明，从进行高通量筛选到获得临床候选药物并进行IND启动研究需要6 - 10年，并且许多项目在实现该目标的不同阶段沿着失败。 根据之前的NS TO（#34），承包商成功证明了向NCI提供至少1种临床候选药物（p97 AAA ATP酶抑制剂）的能力，在申请人终止第二个项目（Mcl-1抑制剂）时，承包商接近提名第二个项目的临床候选药物，以便他们可以与制药公司进行商业化，并且接近提名第三个项目的临床候选药物 因此，在TO-34结束时，我们启动了另一个NS-TO（20-019），其目标与交付至少1个临床候选药物相同。由于可交付成果的性质，只有在筹备过程中进一步沿着的项目才在《NS TO》下得到考虑。出于这个原因，NCI正在提交这个新的NS TO，以允许在管道的早期阶段进行项目，如果成功，将输入到TO 20 -019。此外，该新任务指令还将允许在确定临床候选药物后开展所需的活动，例如扩大规模和生产，以支持IND使能研究和I期临床试验，特别是生物制剂。