Does a new case-based payment system promote the construction of the ordered health delivery system? Evidence from a pilot city in China.

BACKGROUND: The construction of the ordered health delivery system in China aims to enhance equity and optimize the efficient use of medical resources by rationally allocating patients to different levels of medical institutions based on the severity of their condition. However, superior hospitals have been overcrowded, and primary healthcare facilities have been underutilized in recent years. China has developed a new case-based payment method called "Diagnostic Intervention Package" (DIP). The government is trying to use this economic lever to encourage medical institutions to actively assume treatment tasks consistent with their functional positioning and service capabilities. METHODS: This study takes Tai'an, a DIP pilot city, as a case study and uses an interrupted time series analysis to analyze the impact of DIP reform on the case severity and service scope of medical institutions at different levels. RESULTS: The results show that after the DIP reform, the proportion of patients receiving complicated procedures (tertiary hospitals: ß3 = 0.197, P < 0.001; secondary hospitals: ß3 = 0.132, P = 0.020) and the case mix index (tertiary hospitals: ß3 = 0.022, P < 0.001; secondary hospitals: ß3 = 0.008, P < 0.001) in tertiary and secondary hospitals increased, and the proportion of primary-DIP-groups cases decreased (tertiary hospitals: ß3 = -0.290, P < 0.001; secondary hospitals: ß3 = -1.200, P < 0.001), aligning with the anticipated policy objectives. However, the proportion of patients receiving complicated procedures (ß3 = 0.186, P = 0.002) and the case mix index (ß3 = 0.002, P < 0.001) in primary healthcare facilities increased after the reform, while the proportion of primary-DIP-groups cases (ß3 = -0.515, P = 0.005) and primary-DIP-groups coverage (ß3 = -2.011, P < 0.001) decreased, which will reduce the utilization efficiency of medical resources and increase inequity. CONCLUSION: The DIP reform did not effectively promote the construction of the ordered health delivery system. Policymakers need to adjust economic incentives and implement restraint mechanisms to regulate the behavior of medical institutions.

Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase that serves as the negative regulator of multiple immune signaling pathways. Genetic studies using HPK1 knockout and kinase-dead mice suggested that inhibiting HPK1 either alone or in combination with immune checkpoint blockade could be a promising strategy in cancer immunotherapy. Herein, we report the design, synthesis and structure-activity relationship (SAR) study of a series of potent HPK1 inhibitors bearing quinazoline-2,5-diamine scaffold. Three rounds of SAR exploration led to the identification of 9h, the most potent compound in this series which harbors a 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl substituent. Further biological assessments using human immune cells demonstrated that 9h could strongly inhibit downstream phosphorylation, augment interleukin-2 (IL-2) production and reverse prostaglandin E2 (PGE2)-induced immune suppression. Overall, our study on these quinazoline-2,5-diamine derivatives provided not only a tool compound for the community to help with elucidating the HPK1 pharmacology, but also a reliable reference for subsequent development of HPK1 inhibitors.

Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors.

Protein arginine methyltransferase 5 (PRMT5) is a promising target for the treatment of malignant tumors. The discovery of nucleoside-derived inhibitors against PRMT5 with novel scaffold has been challenging. Herein, we report our effort on the design and synthesis of nucleoside derivatives bearing sulfonamide scaffold as potent PRMT5 inhibitors. The representative compound 23n was identified as a potent and selective PRMT5 inhibitor with an IC50 value of 8 nM. Molecular docking study demonstrated the binding mode of compound 23n and illustrated its inhibitory activity to PRMT5. The Trimethyl Lock prodrug strategy was used to afford prodrug 36 with lower polarity which could rapidly release the active compound 23n after entering the tumor cells. Cell-based assays revealed that the prodrug 36 restrained the proliferation of Z-138 and MOLM-13 cells and suppressed methylation of PRMT5 substrate more potently than 23n. Additionally, both compound 23n and 36 exerted antiproliferative effects against Z-138 cells mainly by inducing apoptosis effectively rather than arresting cell cycle. Thus, compounds 23n and 36 represent a series of potent PRMT5 inhibitor with novel scaffold.

Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3-5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development.

Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma.

Although lung adenocarcinoma patients have benefited from the development of targeted therapy, patients with lung squamous cell carcinoma (SqCC) have no effective treatment due to the complexity and heterogeneity of the disease. Therefore, basing on the genetic analysis of mutations in lung squamous cell carcinoma to design multi-target inhibitors represents a potential strategy for the medical treatment. In this study, through screening an in-house focused library, we identified an interesting indazole scaffold. And following with binding analysis, we elaborated the structure-activity relationship of this hit compound by optimizing four parts guided by the DDR2 enzymatic assay, which resulted in a potent lead compound 10a. We conducted further optimization of dual enzymatic inhibitions towards FGFR1 and DDR2, two important kinases in lung squamous cell carcinoma. Finally, from the cellular antiproliferative activity tests and in vivo pharmacokinetic test, 3-substituted indazole derivative 11k was found to be a promising candidate and subjected to in vivo pharmacology study with the mouse xenograft models, demonstrating profound anti-tumor efficacy. Additional in vitro druglike assessment reinforced that compound 11k could be valuable for SqCC drug development.