Inhibition of Bcl-xL by Targeted Degradation

靶向抗凋亡Bcl-2家族蛋白是一种有前途的癌症治疗策略， FDA批准Bcl-2选择性抑制剂venetoclax用于治疗慢性淋巴细胞性白血病 白血病（CLL）和急性髓性白血病（AML）。考虑到Bcl-xL对许多人的重要性， 包括大多数T细胞急性淋巴细胞白血病（T-ALL）在内的癌症类型及其对药物治疗的贡献 由于Bcl-xL的耐药性，Bcl-xL已成为最有效的癌症靶点之一。不幸的是，目标和剂量- 限制与Bcl-xL抑制相关的血小板毒性已经阻止了Bcl-xL抑制剂在抗血小板聚集性疾病中的应用。 诊所为了避免这种毒性，我们应用了蛋白水解靶向嵌合体（PROTAC）技术， 设计小分子靶向Bcl-xL到E3连接酶进行降解。我们的假设是Bcl-xL降解 PROTAC（命名为Bcl-Ps），旨在募集E3连接酶，该酶在血小板中最低限度地表达， 靶向降解Bcl-xL将具有降低的血小板毒性和改善的抗肿瘤活性， 其相应的Bcl-xL抑制剂。这一假设得到了我们强有力的初步结果的支持，包括在 T-ALL患者来源的异种移植（PDX）小鼠模型和其他肿瘤异种移植小鼠中的体内疗效数据 模型此外，我们的Bcl-Ps也是有效的衰老清除剂，可以选择性地杀死衰老细胞（SnC）， 因为SnCs也依赖Bcl-xL生存。化学疗法诱导的SnC的清除被认为是一种有效的方法。 预防或减少化疗药物的许多短期和长期副作用的新策略， 以及癌症复发和转移。总的来说，这些发现表明，Bcl-Ps是上级于 作为抗癌剂的常规Bcl-xL抑制剂。本申请的目标是：（1）优化Bcl-Ps， 改善的效力、选择性、药物样性质和体内功效;（2）通过免疫组织化学评价新的Bcl-Ps。 一系列体外和体内测定;和（3）评价先导Bcl-Ps在T-ALL PDX模型中的临床前功效。 在这个项目完成后，我们的目标是生产Bcl-Ps，以便在T- ALL是一种侵袭性白血病，目前没有靶向治疗。

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.