Search

[Display omitted] • A series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were synthesized as FAK inhibitors. • Compound 7b exhibits potent FAK inhibitory activity with an IC 50 value of 0.27 nM. • Compound 7b arrests cell cycle at G2/M phase and induces cell apoptosis by production of ROS. • Compound 7b can inhibit the clone formation and migration of HCT-116 cells. • Compound 7b has better safety than TAE226. Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC 50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b , 7c , and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 μM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC 50 value of 0.08 μM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b , which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability. [ABSTRACT FROM AUTHOR]

A miniaturized PROTAC named AP-1 with potent activity and high selectivity was discovered by researchers, which greatly reduces the length of linker compared with regular PROTAC. The AP-1 showed strong ALK-degrading activity in ALK-dependent cell lines, and displayed better safety and selectivity than traditional small-molecule inhibitors in ALK-independent cell lines. [Display omitted] • Proteolysis-targeting chimera (PROTAC) for protein degradation can effectively inhibit tumor growth and has the potential to reduce drug resistance. • PROTAC showed better activity than small-molecule inhibitors against mutable proteins and proteins with excessive fusion expression forms. • The miniaturized PROTAC designed by simplest principle can effectively reduce the molecular weight of traditional PROTAC, improve the activity and make up for the deficiency. • The use of ultra-short-linker reduced the overall molecular weight without affecting the activity of PROTAC molecules, resulting in excellent in vivo and in vitro antitumor effects. The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC. [ABSTRACT FROM AUTHOR]

• Novel sulfonamide derivatives containing dithiocarbamate moiety were synthesized as potent PKM2 activators. • Compound 8k has good PKM2 activation potency (AC 50 = 56 nM). • Compound 8k has great anti-proliferation activities on 6 tumor cell lines (IC 50 = 0.28 ~ 1.86 µM). • Compound 8k could effectively inhibit the colony formation of MCF7 cells. • Compound 8k could reduce the PKM2 nuclear localization and block the downstream signaling pathways of PKM2. Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC 50 = 0.136 µM) and 8k (AC 50 = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC 50 = 0.228 µM), and they (IC 50 < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC 50 > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy. [ABSTRACT FROM AUTHOR]