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Tropomyosin receptor kinases (TRK or NTRK) are the transmembrane tyrosine kinases activated by soluble growth factors named neurotrophins (NT). TRK family includes three different members, namely TRKA, TRKB and TRKC. Extracellular recognition of NT to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signal transduction pathways via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRKs are expressed primarily in neuronal tissues and regulate differentiation and survival of neuronal cells. Alteration of TRK pathway caused by gene fusion of TRK is frequently associated with the poor prognosis of a wide range of solid malignancies, such as neuroblastoma, breast cancer, pancreatic cancer, melanoma, thyroid cancer, glioblastoma, colorectal cancer, sarcomas, cholangiocarcinoma, and non-small cell lung cancer. The efficacy of TRK inhibition in TRK fusion-positive cancers has been demonstrated by the high response rate and lasting effect of the first-generation TRK inhibitors larotrectinib and entrectinib. However, acquired resistance mutations of TRK, such as solvent front mutations, gatekeeper mutations and DFG motif mutations, often emerge and abrogate the inhibitory effect of first-generation inhibitors. Thus, developing novel TRK inhibitors that can effectively overcome resistance mutations can provide great clinical benefits to patients. Here we introduce FCN-098, a potent second-generation TRK inhibitor. FCN-098 demonstrated marked kinase inhibition activity against wild-type (WT) and mutant TRK with IC50 at sub-nano or single nanomolar range. FCN-098 significantly and dose-dependently inhibited phosphorylation of TRK and its downstream effector ERK in TRK fusion-positive KM12 human colon cancer cells and BaF3 cells ectopically overexpressing WT or mutant TRK fusions. FCN-098 potently inhibited proliferation of KM12 cells and BaF3 cells overexpressing WT or various mutant TRK fusions while sparing TRK-negative cell lines. Consistent with in vitro results, FCN-098 showed remarkable anti-tumor activity in xenograft models driven by WT or mutant TRK fusions in a dose-dependent manner. In particular, the anti-tumor activity of FCN-098 was superior to another second-generation TRK inhibitor LOXO-195 at the same dose in xenografts driven by TPM3-TRKA G595R or ETV6-TRKC G623R mutation, and exhibited comparable potency to LOXO-195 in LMNA-TRKA G667C-driven xenografts. In non-clinical studies, FCN-098 exhibited excellent pharmacokinetic (PK) and safety properties, demonstrating longer T1/2 in both dogs and rats along with higher Cmax and larger dose-normalized AUC in dogs compared to LOXO-195. Overall, FCN-098 overcomes TRK resistance mutations in vitro and in vivo and exhibits favorable PK and safety profiles. FCN-098 has the potential to become an effective and safe therapeutic choice for a wide range of solid tumors harboring WT or mutant TRK fusions. Citation Format: Shu Lin, Tongshuang Li, Xianlong Wang, Lijun Yang, Zhifang Chen, Yue Rong, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Min Lin, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-098, a novel second-generation TRK inhibitor, overcomes TRK resistance mutations in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3087.

To estimate the radial-forging cropping time accurately, it is essential to obtain the strain fatigue life (SFL) of the metal bar with V-shaped notch. According to the radial-forging cropping mechanism, the relation curve between the fatigue strain and the SFL is constructed. Based on it, a new SFL formula of the metal bar with V-shaped notch, which is related to the fracture ductility of material, the fatigue strain critical value and the stress concentration factor of the V-shaped notch, is proposed. The comparison results for the metal bars show that the relative errors between the results obtained by the new SFL formula and the corresponding experimental results are within 10%.

The influence of atmospheric high consistency refining (AHCR) on the properties of bleached chemical reed pulp was investigated. Fiber quality, water retention value (WRV), dynamic drainage, and physical properties of handsheets were determined. The results showed that compared with low consistency refining (LCR), AHCR maintained reed pulp fiber length, had lower fines generation, produced more fiber curl and kink, and improved WRV and dynamic drainage. Compared with LCR pulp, the tear index, folding strength, and tensile energy absorption (TEA) of AHCR pulp were increased, while tensile index was maintained at the same value. A mill trial was performed to demonstrate the benefits of using AHCR, which was to improve machine runnability and to enhance the performance of the paper made from reed pulp.

In the present study, polysaccharides were extracted from Pharbitis nil seeds (PNSs) by ultrasonic extraction method for the first time. Response surface methodology with Box-Behnken design was used to optimize the extraction process of PNS polysaccharides (PNSPs). Highest PNSPs yield 6.01 ± 0.15% that agreed closely with the predicted yield 5.99% were obtained under the optimal conditions as follows: ratio of water to raw material 6.5 mL/g, extraction temperature 49.0 °C, ultrasonic power 61.6 W, and extraction time 32.6 min. Preliminary characterization indicated that the sugar, uronic acid and protein contents of the product were 83.6 ± 1.61, 21.8 ± 1.25 and 16.4 ± 0.88% (w/w), respectively. FT-IR analysis revealed the general characteristic absorption peaks of polysaccharides. Besides, PNSPs showed a remarkable antioxidant activity in vitro in a dose-dependent manner. These may provide theoretical basis for further system research and rational development and utilization of PNS resources.

Cyclin-dependent kinase-4 (CDK4) and CDK6 form a complex with D-type cyclins to phosphorylate Retinoblastoma protein (Rb), leading to a loss of repression of E2F transcription factors, which enables cell cycle progression from G1 to S phase. Loss of cell cycle control caused by aberrations in CDK/Rb signaling pathway are common in solid tumors. Inhibiting CDK4/6 blocks CDK/Rb signaling pathway, which prevents cell cycle progression through G1 restriction point, thus arresting tumor cell growth. Most of the 1st generation of CDK inhibitors lack CDK family selectivity, and thus result in greater toxicity, and poor efficacy in clinical use. The emergence of a new generation of selective CDK4/6 inhibitors, including FDA approved drugs for ER+/HER2- breast cancer (ribociclib, palbociclib and abemaciclib), has shown clinically meaningful prolongation of progression-free survival over endocrine therapy alone. However, the treatment is limited for patients with brain metastases, because the blood-brain barrier (BBB) penetration of approved CDK4/6 inhibitors are either restricted, or lack of clinical assessment. Therefore, it is urgently needed to develop novel CDK4/6 inhibitors with improved effectiveness, better BBB penetration and fewer adverse effects. Here, we developed FCN-437, a novel, selective and orally active inhibitor of CDK4/6. FCN-437 has demonstrated selective inhibitory activities against CDK4/6 over other CDKs. FCN-437 has shown broad-spectrum anti-proliferating activity on Rb+ tumor cells, derived from tissues of various solid tumors. The in vitro potency of FCN-437 is 5-fold more than ribociclib, and comparable to palbociclib. Correspondingly, in tumor xenograft models of breast cancer, colon cancer and glioma, FCN-437 dramatically inhibited tumor growth, comparable or superior to approved CDK4/6 inhibitors. FCN-437 possesses good synergetic effect in combination with letrozole or fulvestrant in vivo. FCN-437 exhibits excellent pharmacokinetic (PK) properties with improved bioavailability. In particular, FCN-437 preferentially distributes to tissues including brain compared to plasma in rats, indicating improved BBB permeability, which provides an opportunity to treat tumors that have metastasized to the brain. In non-clinical studies, FCN-437 has shown preferable safety profiles with low hERG activity and no potential cardiotoxicity. No CYP450 inducing or inhibiting effect was found in FCN-437, minimizing its potential of drug interactions. Overall, FCN-437 exhibits desired drug-like properties, enhanced efficacy, improved PK properties with BBB penetration and preferable safety profiles compared to approved CDK4/6 inhibitors. FCN-437 can be a novel and effective targeted therapy either as single agent or in combination, for patients with advanced solid tumors with brain metastases. A phase 1 clinical trial of FCN-437 has been granted approval by NMPA in 2018. Citation Format: Shu Lin, Xingdong Zhao, Tongshuang Li, Huajie Zhang, Haohan Tan, Xianlong Wang, Lihua Jiang, Yanxin Liu, Jing Sun, Li Linghu, Qihong Liu, Zhifu Li, Weipeng Zhang, Weibo Wang. FCN-437: A novel, potent and selective oral inhibitor of CDK4/6 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4425.

B-cell lymphoma-2 (Bcl-2) family proteins are key regulators of apoptosis, which is vital for proper tissue development and cellular homeostasis. Apoptosis occurs via activation of two different pathways: the extrinsic pathway, triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR1; and the intrinsic pathway, regulated by Bcl-2 family proteins and their complex protein-protein interactions. Bcl-2 family proteins are functionally classified as either anti-apoptotic, such as Bcl-2, Bcl-xL and Mcl-1, or pro-apoptotic, including Bid, Bim, Bad, Bak and Bax. Anti-apoptotic Bcl-2 family members are often found to be up-regulated in many types of human cancers, such as different subtypes of B-cell lymphoma and diverse solid tumors, and are frequently been correlated with decreased susceptibility to chemotherapeutics and to increased radio-resistance. Overexpression of Bcl-2 proteins is an independent indicator of poor prognosis in tumors including chronic lymphocytic leukemia (CLL), prostate cancer, and small cell lung cancer (SCLC). Therefore, targeting Bcl-2 and its pro-survival relatives that form the core anti-apoptotic machinery, has emerged as a promising therapeutic approach in cancer. To that end, we have developed a novel and selective Bcl-2 inhibitor, FCN-338, with nanomolar affinity to Bcl-2 and physicochemical properties suitable for oral administration. FCN-338 exhibits much greater affinity to Bcl-2 than Bcl-xL, suggesting its good potential to avoid thrombocytopenia caused by the inhibition of Bcl-xL. FCN-338 has shown remarkable anti-proliferation potency against a panel of Bcl-2-addicted human B-cell lymphoma cell lines, including DOHH2 follicular lymphoma (FL) cell line (IC50 2 nM), Mino diffuse large B-cell lymphoma (DLBCL) cell line (IC50 23 nM), and RS4;11 acute lymphoblastic leukemia (ALL) cell line (IC50 35 nM), but not in Bcl-xL-dependent H146 SCLC cell line (IC50 >4,500 nM). Correspondingly, in vivo efficacy of FCN-338 was demonstrated in a variety of xenograft models derived from FL, DLBCL and ALL tumors. FCN-338 dramatically caused tumor regression in a dose-dependent manner. In the non-clinical studies, FCN-338 exhibits much improved pharmacokinetic properties with higher T1/2, dose-normalized AUC and bioavailability in dogs compared with the FDA-approved Bcl-2 inhibitor ABT-199. Preferable safety profiles of FCN-338 were shown with no potential hERG inhibitory effect and less drug-drug interaction potential, as evidenced by no inhibitory effect (IC50 >50 μM) on CYP2C9 enzyme compared with ABT-199 (IC50 1.05 μM). Together, our findings highlight the therapeutic potential of FCN-338 to be used as effective therapy across a broad range of Bcl-2-addicted B-cell malignancies. Citation Format: Shu Lin, Xingdong Zhao, Hongbin Liu, Huajie Zhang, Zhifang Chen, Lihua Jiang, Yanxin Liu, Min Lin, Yue Rong, Rui Tan, Zuwen Zhou, Zongyao Zou, Yuwei Gao, Weibo Wang. FCN-338, a novel and selective Bcl-2 inhibitor, exhibits potent anti-tumor activity in B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2497.