Discovery and Evaluation of 3-Quinoxalin Urea Derivatives as Potent, Selective, and Orally Available ATM Inhibitors Combined with Chemotherapy for the Treatment of Cancer via Goal-Oriented Molecule Generation and Virtual Screening.

ATM plays an important role in DNA damage response and is considered a potential target in cancer therapies. In this study, a goal-directed molecular generation approach based on ligand similarity and target specificity was applied to sample active molecules, and they were screened virtually to identify the theoretical lead compound 7a, which was later shown to inhibit ATM adequately. However, there is a main concern about its poor metabolic stability in vitro. Subsequent optimization was performed to improve the potency and selectivity toward ATM and attenuate the hepatic clearance in vitro, culminating in the identification of 10r with nanomolar ATM inhibition, excellent cellular sensitivity to radiation and chemotherapy drugs, and impressive pharmacokinetic profiles. Furthermore, 10r combined with irinotecan demonstrated a synergistic antitumor efficacy in SW620 xenograft models, suggesting that it could be a promising candidate drug combined with chemotherapy for the treatment of cancer.

Discovery of indoline-based derivatives as effective ROCK2 inhibitors for the potential new treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease with a median survival of only 3-5 years. Due to the lack of effective therapy, IPF threatens human health. Recently, increasing reports have indicated that Rho-associated coiled-coil protein kinases (ROCKs) play important roles in the development of IPF and might represent a novel target for the treatment of IPF. Herein, a new series of selective ROCK2 inhibitors based on indoline were designed and synthesized. Structural modification resulted in optimized compound 9b with an IC50 value of 6 nM against ROCK2 and the inhibition of collagen gel contraction. Cellular assays demonstrated that 9b could significantly suppress the expression of collagen I and α-SMA, and inhibited ROCK signaling pathway. Oral administration of compound 9b (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than nintedanib (100 mg/kg) and KD025 (100 mg/kg) in a bleomycin-induced IPF rat model, suggesting that 9b could serve as a potential lead compound for the treatment of IPF.

Design, synthesis and biological evaluation of purine-based derivatives as novel JAK2/BRD4(BD2) dual target inhibitors.

Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC50 values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/ß signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3-JAK2V617F allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases.

Impact of Charge Composition and Distribution on the Antibacterial Properties of Polypeptide Coatings.

Inspired by the charge composition and distribution of proteins and peptides, we designed and prepared a series of brush polypeptides with positive and negative charges separately distributed in the side chains and the backbones. The brush polypeptides can self- or co-deposit on various substrates forming ultrathin and stable coatings. They showed potent bactericidal activity and antibiofilm property, outperforming conventional linear polypeptide coatings with randomly distributed positive and negative charges. Keeping the balance of positive/negative charges and increasing the numbers of positive/negative charges can further improve the antibacterial property of brush polypeptide coatings without sacrificing their biocompatibility.

SKLB-14b, a novel oral microtubule-destabilizing agent based on hydroxamic acid with potent anti-tumor and anti-multidrug resistance activities.

A hydroxamic acid based microtubule-destabilizing agent (MDA) SKLB-14b was discovered in this study, which was derived from shortening the linker length of the HDAC6 and microtubule dual-target inhibitor SKLB-23bb. SKLB-14b exhibited low nanomolar IC50 values on a wide spectrum of human cancer cell lines including both sensitive and multidrug-resistant cell lines. Surprisingly, its anti-proliferative activity relied on the presence of the hydroxamic acid group but lost inhibitory activity against HDACs. SKLB-14b bound to the colchicine site of tubulin and could inhibit tubulin polymerization. It exhibited good metabolic stability in liver microsomes, no inhibitory effect on CYP450 isoenzymes and high oral bioavailability. In vivo experiments revealed that SKLB-14b was potent in both sensitive (A2780S, HCT116) and resistant (A2780/T) xenograft mice models. Furthermore, in the patient-derived tumor xenograft (PDX) models of osimertinib resistant non-small cell lung cancer (NSCLC), 50 mg/kg of SKLB-14b administered every twodays inhibited tumor growth by 70.6% without obvious toxicity, better than the 59.7% inhibition rate of paclitaxel. Mechanistically, we found that SKLB-14b exerted anti-tumor and anti-multidrug resistance effects in vitro and in vivo through cell cycle arrest and pro-apoptotic activities, as well as vascular disrupting activities. Therefore, we discovered that SKLB-14b, as a novel MDA based on hydroxamic acid, could serve as a potential drug candidate for cancer therapy which deserves further investigation.

Facile Preparation of Polysaccharide-Polypeptide Conjugates via a Biphasic Solution Ring-Opening Polymerization.

Polysaccharide-polypeptide conjugates have gained a broad interest in mimicking the structure and bioactivity of peptidoglycans or proteoglycans for biomedical applications. Efficient and precise preparation of the conjugates is challenging and unresolved, mainly because of the mismatched solubility between polysaccharide initiators and N-carboxyanhydrides (NCAs), which frequently results in competing side reactions and oligomeric polypeptide chain. Herein, we report a facile and efficient strategy to prepare the conjugates with well-controlled polypeptide chain length (lp) directly from unmodified polysaccharides via a biphasic solution ring-opening polymerization. The effect of lp on surface antibacterial properties has been investigated. Elongating the lp can significantly potentiate the antibiofilm property of the conjugate coatings. Our results may provide opportunities to develop various polypeptide-based conjugates with well-defined structures toward versatile uses.

Design, synthesis and biological evaluation of novel FAK inhibitors with better selectivity over IR than TAE226.

In this study, 28 novel focal adhesion kinase (FAK) inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 18b displayed good inhibition of FAK (IC50 = 45 nM) with at least 22 fold of selectivity over insulin receptor (IR, IC50 > 1000 nM) and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC50 values of 0.27, 0.19 and 0.26 µM respectively, compared to TAE226 (2.68, 0.64 and 4.19 µM respectively). 18b also inhibited the clone formation and migration of HCT-116 cells, tube formation of HUVECs, and stimulated cell cycle arrest in the G2/M phase, inducing apoptosis by promoting ROS production. The FAK-Src-ERK signaling pathway was inhibited by 18b in a dose-dependent manner. Moreover, 18b showed adequate oral bioavailability of 16.37% and 75.90% tumor growth inhibition in the HCT116 xenograft model was observed. These results indicate that 18b is a promising selective inhibitor of FAK.

Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors.

FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.

Design, synthesis, and biological evaluation of novel covalent inhibitors targeting focal adhesion kinase.

Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC50 value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC50 values of 0.41, 0.01 and 0.11 µM respectively, compared to TAE226 (2.68, 0.64 and 4.19 µM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G2/M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK.

Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity.

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, 12b showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of 12b could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that 12b, as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.

Deactivation Kinetics of Polyethylenimine-based Adsorbents Used for the Capture of Low Concentration CO2.

CO2 emission is generally regarded as the major contributor to global climate change, and polyethylenimine (PEI)-based CO2 adsorbents are promising materials for the capture of low concentration CO2. This paper deals with the deactivation kinetics of PEI-based CO2 adsorbents used for the capture of low concentration CO2. EA and TG analyses demonstrated that thermal degradation and O2-induced deactivation of the adsorbents occurred simultaneously under air exposure conditions. It was found by N2 exposure experiments at the temperature of 50-80 °C that the thermal degradation of PEI-based adsorbents followed a first-order reaction model with an activation energy of 80.98 kJ/mol and a pre-exponential factor of 6.055 × 108 (h-1). The parallel reaction model was employed to distinguish the O2-induced deactivation from the thermal degradation of the adsorbents through air exposure experiments within 50-80 °C. The O2-induced deactivation exhibited a second-order reaction with an activation energy of 74.47 kJ/mol and a pre-exponential factor of 6.321 × 106 (%-1·h-1). The results of simulating the overall deactivation of the adsorbents by the parallel reaction kinetic model were well consistent with those of the experiments, proving that the parallel reaction model was feasible for the description of the deactivation of PEI-based adsorbents.