Non-peptide proteasome inhibitors as a novel anticancer agent

描述（由申请人提供）：该项目的长期目标是开发下一代蛋白酶体抑制剂，该抑制剂将作为1)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)实体癌患者的有效疗法。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）和卡非佐米（Kyprolis）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作为一个重要的抗癌靶点。然而，许多患者在长期的蛋白酶体抑制剂治疗后最终产生耐药性，并且对于这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临床前模型中具有良好的抗癌活性，但它们在实体癌治疗方面的潜力仍未得到开发。因此，开发新的蛋白酶体抑制剂，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疗效传递给包括实体癌在内的所有类型的癌症患者，是至关重要的。我们假设，一类新的蛋白酶体抑制剂与非肽支架将为耐硼替佐米或卡非佐米的MM患者和实体癌患者提供新的治疗选择。这是基于硼替佐米、卡非佐米和几乎所有蛋白酶体抑制剂在药物开发管道中共享的结构特征所产生的缺陷。具体来说，肽骨架和反应性药效团的结构特征有助于对化学/代谢失活和脱靶相互作用的高度敏感性，从而导致不必要的毒性和无法在实体癌症部位实现充分的药物渗透。利用虚拟筛选和体外酶动力学相结合的逐步筛选方法，我们确定了几种具有不同非肽支架和蛋白酶体抑制能力的有希望的hit。G4-1是一种1,3,5取代吡唑衍生物，是我们目前的主要候选药物，它在多种癌细胞系中显示出抗癌活性，包括对硼替佐米或卡非佐米耐药的细胞系。除了拥有优秀

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.