Pre-IND Study of Pz-1, a dual pan-RET/VEGFR2 inhibitor for the Treatment of RET-driven Disease

Pz-1 的 IND 前研究，一种双重泛 RET/VEGFR2 抑制剂，用于治疗 RET 驱动的疾病

• 批准号: 8902059
• 负责人: Brendan Andrew Frett
• 金额: $ 30万
• 依托单位: SYNACTIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902059
• 关键词: 2-tyrosine; Adaptor Signaling Protein; Adverse effects; Arizona; Bioavailable; Biopsy; CYP2D6 gene; CYP3A4 gene; Cancer Patient; Canis familiaris; Cells; Clinical; Data; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Drug Packaging; Excipients; Gatekeeping; Generations; Growth; Hour; Inhibitory Concentration 50; MAP Kinase Gene; Malignant Neoplasms; Marketing; Mediating; Medicine; Methods; Monitor; Mus; Mutation; Nutrient; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plant Roots; Plasma; Property; Rattus; Research; Services; Signal Transduction; Sodium Chloride; Solubility; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicokinetics; Transfection; Tyrosine Kinase Inhibitor; Universities; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model; Xenograft procedure; angiogenesis; aqueous; clinically relevant; design; drug development; effective therapy; improved; inhibitor/antagonist; medullary thyroid carcinoma; organic acid; pre-clinical; protein activation; public health relevance; small molecule; tumor; tumor growth; tumor xenograft

 DESCRIPTION (provided by applicant): Polypharmacology represents a new and attractive approach to treat malignances, as lasting and robust efficacy could be obtained through the inhibition of multiple survival pathways with one therapeutic agent. In line with this method, we have designed a RET (rearranged during transfection) / VEGFR2 (vascular endothelial growth factor receptor 2) small molecule inhibitor that can shut down RET prosurvival signaling and VEGFR2 mediated angiogenesis. With this agent, the root of oncogenic signaling within RET-driven tumors can be shut down as well as the ability for a tumor to acquire nutrients through VEGFR2. The inhibitor can achieve activity on RET, VEGFR2, and all clinically relevant RET mutations at IC50s of = 1.0 nM. Through a PO 0.3 mg/kg/day dose, the inhibitor can block growth and cause RET-driven xenografts to shrink. Astonishingly, at a PO 3.0 mg/kg/day dose, all treated tumors recede to undetectable levels in 28 days. In xenograft models highly predictive of clinical activity, our agent is >100 times more active than similar agents. We determined inhibition of both RET and VEGFR2 in tumor xenografts and found at PO 1.0 mg/kg our agent completely blocks RET and VEGFR2 activity. Signaling to RET and VEGFR2 adaptor proteins and activation of the MAPK cascade is inhibited as well. Pathway inhibition of both RET and VEGFR2 has been correlated to observed efficacy. The inhibitor was found to be 97% bioavailable in rats with a T1/2 of ~4 hours. The agent was minimally active on hERG with IC50 of 10.0 µM, CYP3A4 with IC50 = 4-10 µM, and CYP2D6 with IC50 = 13 µM. Inhibition of proliferative growth and proliferative signals was found highly selective for RET-driven tumors. GI50s for RET- driven tumors were typically <1.0 nM. No adverse effect was identified in a 7 day toxicity study at PO 100 mg/kg/day in mice indicating a large therapeutic window. The agent achieves activity on all ten clinically relevant RET mutations tested, including gatekeeper mutations, at IC50s = 1.0 nM. We believe the unique properties of our agent to simultaneously block all RET-driven tumor growth and suppress VEGFR2 mediated nutrient accumulation is responsible for the unparalleled efficacy, which could result in improved patient survival. In this proposal, we wish to further develop our RET/VEGFR2 dual inhibitor by completing pilot formulation, PK/PD, and toxicity studies. This will acquire pivotal data necessary to justify completing an investigative new drug (IND) package. Although we have established a robust 'proof of concept' data package, specific facets to preclinical development are lacking that warrant additional pre-IND development. With the completion of this proposal, we will have a data package that will merit full IND development.

 描述(由申请人提供)：多元药理学代表了一种治疗恶性肿瘤的新的和有吸引力的方法，因为通过用一种治疗剂抑制多条生存途径可以获得持久和强大的疗效。根据这种方法，我们设计了一种RET/VEGFR2(血管内皮生长因子受体2)小分子抑制剂，可以阻断RET的生存信号和VEGFR2介导的血管生成。有了这种药物，RET驱动的肿瘤内致癌信号的根源可以被关闭，肿瘤通过VEGFR2获得营养的能力也可以被关闭。该抑制剂可在=1.0 nM的IC50达到对RET、VEGFR2和所有临床相关RET突变的活性。通过PO 0.3 mg/kg/天的剂量，该抑制剂可以阻止生长并使RET驱动的异种移植物收缩。令人惊讶的是，在PO 3.0 mg/kg/天的剂量下，所有治疗的肿瘤在28天内都消退到无法检测到的水平。在高度预测临床活动的异种移植模型中，我们的试剂的活性是类似药物的100倍。我们检测了RET和VEGFR2在肿瘤移植瘤中的抑制作用，发现在PO 1.0 mg/kg时，我们的试剂完全阻断了RET和VEGFR2的活性。对RET和VEGFR2接头蛋白的信号传导和MAPK级联的激活也被抑制。RET和VEGFR2的通路抑制与观察到的疗效相关。该抑制剂在大鼠体内的生物利用度为97%，t1/2为~4小时。该药物对HERG的IC50为10.0微米，对CYP3A4的IC50为4-10微米，对CYP2D6的IC50为13微米。对于RET驱动的肿瘤，抑制增殖生长和增殖信号具有高度的选择性。RET驱动肿瘤的GI50通常为1.0纳米。PO 100 mg/kg/d对小鼠进行了7天的毒性研究，未发现不良反应，表明有较大的治疗窗口。该试剂在IC50=1.0 nM时对所有10个临床相关的RET突变进行测试，包括把关突变。我们相信，我们的制剂具有同时阻止所有RET驱动的肿瘤生长和抑制VEGFR2介导的营养积累的独特特性，这是产生无与伦比的疗效的原因，这可能会提高患者的存活率。在这 我们希望通过完成中试配方、PK/PD和毒性研究，进一步开发我们的RET/VEGFR2双重抑制剂。这将获得必要的关键数据，以证明完成一项研究新药(IND)包的合理性。虽然我们已经建立了一个强大的“概念验证”数据包，但临床前开发的特定方面缺乏保证额外的IND前期开发。随着这项提议的完成，我们将拥有一个值得充分开发的数据包。