br Disclosure br Acknowledgments br

Disclosure
Acknowledgments
Introduction Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, belongs to the insulin receptor kinase subfamily [1]. Oncogenic activation of ALK is associated with the THZ1 Hydrochloride and progression of multiple human cancer types [2,3], including anaplastic large-cell non-Hodgkin's lymphoma (ALCL) [1], non-small-cell lung cancer (NSCLC) [4], inflammatory myofibroblastic tumor (IMT) [5], diffuse large B cell lymphoma (DLBCL) [6], squamous cell carcinoma (SCC) [7], renal cell carcinoma (RCC) [8], thyroid cancer [9], breast cancer [10], colon carcinoma [10], ovarian cancer [11], and neuroblastoma [[12], [13], [14], [15]]. Three different mechanisms have been reported to active the ALK kinase [2]. The most common genetic alterations in this gene are chromosomal translocations, which result in constitutive activation of the ALK kinase. Nearly 30 different ALK fusion proteins have been identified [3]. Two of them, NPM-ALK and EML4-ALK, have been extensively studied in ALCL [1] and NSCLC [4], respectively. The second mechanism for ALK activation is through substitution mutations. Hotspot mutations at residues, F1174 and R1275, at the kinase domain are most commonly observed in patients with neuroblastoma [16]. The third ALK activation mechanism involves gene amplification and overexpression, which has also been reported in different human cancers [[17], [18], [19], [20]]. For example, co-amplification of ALK and MYCN has been reported as the oncogenic driver in neuroblastoma [16,21]. Significant efforts have been devoted to the development of therapeutics that inhibit the kinase catalytic activity of ALK. To date, four ALK inhibitors have been approved by the FDA for treating patients with ALK-positive NSCLC, including 1 (crizotinib), 2 (ceritinib), 3 (alectinib), and 4 (brigatinib) (Fig. 1) [22]. Various clinical trials are ongoing to investigate potential applications of these drugs in the treatment of other diseases linked to ALK alterations [22]. Clinical results have demonstrated that patients with ALK-positive lung cancer showed remarkable responses and increased progression-free survival when treated with ALK inhibitors 1 [23,24], 2 [25], and 3 [26,27]. Despite the initial response to such treatments, the majority of these patients eventually develop resistance to these drugs within 1–2 years [22,28]. Hence, developing new therapeutic approaches to delay or overcome drug resistance is needed. Proteolysis-targeted chimeras (PROTACs) are hetero-bifunctional small molecules that are aimed at achieving selective degradation of the target proteins [[29], [30], [31], [32]]. Typically, PROTACs (also known as degraders) include one moiety that binds the protein target of interest, another that binds an E3 ubiquitin ligase, and a linker that connects these two moieties. Simultaneous binding of the target protein and an E3 ubiquitin ligase by a PROTAC brings the target protein close enough to the E3 ligase, enabling ubiquitination and subsequent 26 S proteasome-dependent degradation [30]. While traditional enzyme inhibitors only inhibit the catalytic activity of the target enzyme, PROTACs bind and induce degradation of the enzyme, thus eliminating potential scaffolding functions of the protein, in addition to inhibiting the enzymatic activity [29]. The PROTAC technology has been successfully applied to selective degradation of multiple targets, including kinases. Besides a couple of pan kinase PROTACs [33,34], most of kinase PROTACs reported to date target specific kinases, such as RIPK2 [35], BCR-ABL [36,37], CDK9 [38,39], TBK1 [40], FLT3 [33], BTK [33], EGFR [41], HER2 [41], and c-Met [41]. ALK is an ideal target for developing PROTACs. While ALK activation is found in multiple types of human cancer, ALK is predominantly expressed throughout the nervous system during embryogenesis and its expression is very low in normal adult tissues [2,42]. In addition, ALK is not required for viability in mammals, as mice with ALK deletion are viable with only mild behavior phenotypes, such as antidepressant profile, enhanced performance in novel object-recognition, and enhanced spatial memory [43,44]. Therefore, pharmacological degradation of ALK is expected to display minimal toxicity in the clinic and could provide a novel, potential therapeutic strategy for patients with ALK-positive cancers.