Non-peptide proteasome inhibitors as a novel anticancer agent

描述(申请人提供)：该项目的长期目标是开发下一代蛋白酶体抑制剂，用于1)对现有蛋白酶体靶向药物bortezomib和carfilzomib无效的多发性骨髓瘤(MM)患者以及2)实体癌症患者。在过去的十年中，FDA已经批准了蛋白酶体靶向药物bortezomib(VELCADE(R))和carfilzomib(Kyprolis(R))用于治疗MM患者。这些药物极大地改善了MM的预后，并坚定地证实了蛋白酶体是一个重要的抗癌靶点。然而，许多患者在长期接受蛋白酶体抑制剂治疗后最终产生耐药性，对这些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良好的抗癌活性，但其在实体癌治疗中的潜力仍未被开发。因此，开发新的蛋白酶体抑制剂非常重要，它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治疗的益处传递给包括实体癌在内的所有类型的癌症患者。我们推测，一类新的蛋白酶体抑制剂和非肽支架将为对博替佐米或卡菲佐米无效的多发性骨髓瘤患者和实体肿瘤患者提供新的治疗选择。这是基于Bortezomib、carfilzomib和药物开发管道中几乎所有蛋白酶体抑制剂的共同结构特征所产生的缺陷。具体地说，多肽骨架和活性药效团的结构特征导致了对化学/代谢失活和靶外相互作用的高度敏感性，导致不必要的毒性和无法在固体癌症部位实现足够的药物渗透。使用虚拟筛选和体外酶动力学相结合的逐步筛选方法，我们鉴定了几个具有不同非肽支架和蛋白酶体抑制活性的有希望的HIT。G4-1是一种1，3，5-取代吡唑类化合物，是我们目前的首选候选化合物，在多个癌细胞株中显示了其抗癌活性，包括对bortezomib或carfilzomib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效果和安全性。使用 为了进一步提高G4-1的效力和其他药代动力学特性，使其适合口服给药，我们提出了以下目标：1)扩大我们的领先优化努力 在开发更有效的、具有更好的类药物性质的蛋白酶体抑制剂方面，2)研究优化的非肽蛋白酶体抑制剂的细胞毒性作用机制，以及3)评价选定的先导型非肽蛋白酶体抑制剂的体内抗癌效果、安全性和药代动力学。拟议工作的成功完成将产生新型非肽蛋白酶体抑制剂，可以推进药物开发的下一阶段，并最终为多发性骨髓瘤和实体癌症患者带来有效的治疗方法。

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.