Inhibition of Bcl-xL by Targeted Degradation

靶向抗凋亡的Bcl-2家族蛋白是一种很有前途的癌症治疗策略，已被 被FDA批准用于治疗慢性淋巴细胞的Bcl2选择性抑制剂ventoclax 白血病(CLL)和急性髓系白血病(AML)。鉴于Bclxl对许多人的重要性已经得到了充分的证明 癌症类型，包括大多数T细胞急性淋巴细胞白血病(T-ALL)，及其对药物的贡献 耐药，Bclxl已成为最有效的癌症靶点之一。不幸的是，靶点和剂量- 限制与抑制Bclxl相关的血小板毒性阻止了Bclxl抑制剂在 诊所。为了规避这种毒性，我们将蛋白水解靶向嵌合体(PROTAC)技术应用于 设计以Bclxl到E3连接酶为靶点的小分子进行降解。我们的假设是Bc l-xl降解 PROTAC(命名为Bcl-Ps)旨在招募一种在血小板中最低水平表达的E3连接酶，用于 靶向降解Bcl-xL将降低血小板毒性并提高抗肿瘤活性 其相应的Bc l-xl抑制剂。这一假设得到了我们强劲的初步结果的支持，包括在 T-ALL患者来源的异种移植(PDX)小鼠模型和其他肿瘤移植模型的体内疗效数据 模特们。此外，我们的Bcl-Ps也是有效的感光剂，可以选择性地杀死衰老细胞(SNCs)。 因为SNCs的生存也依赖于Bclxl。清除化疗诱导的SNCs被认为是一种 预防或减少化疗药物的许多短期和长期不良反应的新战略， 以及癌症复发和转移。总而言之，这些发现表明，BclPs优于 传统的Bcl-xl抑制剂作为抗癌药物。此应用程序的目标是：(1)为以下目标优化BCL-Ps 提高效力、选择性、类药物特性和体内疗效；(2)通过 (3)在T-ALL PDX模型中评价BclPs铅的临床前疗效。 该项目完成后，我们的目标是生产出可在T-P临床试验中进一步评估的Bc l-Ps。 ALL是一种侵袭性白血病，目前还没有靶向治疗。

Targeting the anti-apoptotic Bcl-2 family proteins is a promising therapeutic strategy for cancer and has been validated by the FDA approval of the Bcl-2 selective inhibitor, venetoclax, for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Given the well-documented importance of Bcl-xL to many types of cancers, including most T-cell acute lymphoblastic leukemia (T-ALL), and its contribution to drug resistance, Bcl-xL has become one of the best validated cancer targets. Unfortunately, the on-target and dose- limiting platelet toxicity associated with the inhibition of Bcl-xL has prevented the use of Bcl-xL inhibitors in the clinic. To circumvent this toxicity, we have applied the Proteolysis Targeting Chimera (PROTAC) technology to design small-molecules that target Bcl-xL to E3 ligases for degradation. Our hypothesis is that Bcl-xL degrading PROTACs (named as Bcl-Ps) designed to recruit an E3 ligase that is minimally expressed in platelets for the targeted degradation of Bcl-xL will have reduced platelet toxicity and improved antitumor activity compared with their corresponding Bcl-xL inhibitors. This hypothesis is supported by our strong preliminary results, including in vivo efficacy data in T-ALL patient-derived xenograft (PDX) mouse models and other tumor xenograft mouse models. In addition, our Bcl-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs), because SnCs also rely on Bcl-xL for survival. Clearance of chemotherapy-induced SnCs is considered as a novel strategy to prevent or reduce many short- and long-term adverse effects of the chemotherapeutic drugs, as well as cancer relapse and metastasis. Collectively, these findings suggest that Bcl-Ps are superior to conventional Bcl-xL inhibitors as anticancer agents. The goal of this application is to: (1) optimize Bcl-Ps for improved potency, selectivity, drug-like properties, and in vivo efficacy; (2) evaluate the new Bcl-Ps through a series of in vitro and in vivo assays; and (3) evaluate the preclinical efficacy of lead Bcl-Ps in T-ALL PDX models. Upon completion of this project, we aim to produce Bcl-Ps amenable to further evaluation in clinical trials for T- ALL, an aggressive leukemia that currently has no targeted therapies.