Non-peptide proteasome inhibitors as a novel anticancer agent

描述（由申请方提供）：本项目的长期目标是开发下一代蛋白酶体抑制剂，其将作为有效疗法1）用于对现有蛋白酶体靶向药物硼替佐米和卡非佐米难治的多发性骨髓瘤（MM）患者以及2）用于实体癌患者。在过去的十年中，FDA已经批准了蛋白酶体靶向药物硼替佐米（Velcade（R））和卡非佐米（Kyprolis（R））用于治疗MM患者。这些药物极大地改善了MM的预后，并坚定地验证了蛋白酶体作为一个重要的抗癌靶点。然而，许多患者在长期蛋白酶体抑制剂治疗后最终会产生耐药性，并且此类患者几乎没有有效的治疗选择。此外，尽管蛋白酶体靶向药物在实体癌的临床前模型中具有很好的抗癌活性，但其治疗实体癌的潜力仍未开发。因此，至关重要的是开发新的蛋白酶体抑制剂，其可以克服现有蛋白酶体抑制剂的局限性，并将蛋白酶体抑制剂疗法的治疗益处递送给所有类型的癌症患者，包括实体癌。我们假设，一类新的蛋白酶体抑制剂与非肽支架将提供新的治疗选择的MM患者难治性硼替佐米或carfilzalide和实体癌患者。这是基于硼替佐米、卡非佐米和药物开发管道中几乎所有蛋白酶体抑制剂之间共有的结构特征所产生的缺点。具体而言，肽骨架和反应性药效团的结构特征导致对化学/代谢失活和脱靶相互作用的高度敏感性，从而导致不需要的毒性和无法在实体癌部位内实现足够的药物渗透。使用逐步筛选方法结合虚拟屏幕和体外酶动力学，我们确定了几个有前途的命中与不同的非肽支架和蛋白酶体抑制效力。G4-1是一种1，3，5-取代的吡唑衍生物，是我们目前的主要候选药物，在多种癌症细胞系中显示出其抗癌活性，包括对硼替佐米或卡非佐米耐药的细胞系。除了拥有出色的 G4-1在体内表现出良好的抗癌功效和安全性。与 为了进一步改善G4-1的效力和其他药代动力学性质以适合口服给药，我们提出了以下目标：1）扩展我们的先导优化努力 开发具有改善的药物样特性的更有效的蛋白酶体抑制剂，2）研究优化的非肽蛋白酶体抑制剂的细胞毒性作用机制，和3）评价选定的先导非肽蛋白酶体抑制剂的体内抗癌功效、安全性和药代动力学特征。拟议工作的成功完成将产生新型非肽蛋白酶体抑制剂，这些抑制剂可以进入下一阶段的药物开发工作，并最终为MM和实体癌患者提供有效的治疗方法。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop next-generation proteasome inhibitors that will serve as effective therapies 1) for multiple myeloma (MM) patients refractory to the existing proteasome-targeting drugs bortezomib and carfilzomib as well as 2) for patients with solid cancers. In the last decade, the FDA has approved the proteasome-targeting drugs, bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) for the treatment of MM patients. These agents have greatly improved the prognosis of MM and firmly validated the proteasome as an important anticancer target. However, many patients eventually develop resistance after prolonged proteasome inhibitor therapy and few effective treatment options exist for such patients. In addition, the potential of proteasome-targeting drugs remain untapped for the treatment of solid cancers, despite their promising anticancer activities in preclinical models of solid cancers. Thus, it is critically important to develop novel proteasome inhibitors which can overcome the limitations of existing proteasome inhibitors and deliver the therapeutic benefits of proteasome inhibitor therapy to cancer patients of all types including solid cancers. We hypothesize that a new class of proteasome inhibitors with non-peptide scaffolds will provide new therapeutic options for MM patients refractory to bortezomib or carfilzomib and solid cancer patients. This is based on the drawbacks arising from the structural features shared among bortezomib, carfilzomib and nearly all proteasome inhibitors in drug development pipelines. Specifically, the structural features of peptide backbones and reactive pharmacophores contribute to a high susceptibility to chemical/metabolic inactivation and off-target interactions causing unwanted toxicities and an inability to achieve sufficient drug penetration within solid cancer sites. Using step-wise screening approaches combining virtual screen and in vitro enzyme kinetics, we identified several promising hits with diverse non-peptide scaffolds and proteasome inhibitory potencies. G4-1, a 1,3,5-substitutive pyrazole derivative is our current lead candidate, displaying its anticancer activity in multiple cancer cel lines, including cell lines resistant to bortezomib or carfilzomib. In addition to having excellent metabolic stability, G4-1 displayed promising anticancer efficacy and safety profiles in vivo. With the goal of further improving the potency and other pharmacokinetic properties of G4-1 to be suitable for oral dosing, we propose the following aims: 1) to extend our lead optimization efforts in developing more potent proteasome inhibitors with improved drug-like properties, 2) to investigate the cytotoxic mechanism of action of optimized non-peptide proteasome inhibitors, and 3) to evaluate the in vivo anticancer efficacy, safety and pharmacokinetic profiles of selected lead non-peptide proteasome inhibitors. Successful completion of the proposed work will yield novel non-peptide proteasome inhibitors that can advance to next stages of drug development efforts and ultimately lead to effective therapies for patients with MM and solid cancers.