Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFRdel19/T790M/C797S and EGFRL858R/T790M/C797S).

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated encouraging clinical outcomes for patients with EGFR-mutated non-small cell lung cancer, a considerable number of patients will develop drug resistance and eventually undergo disease progression after taking EGFR-TKIs for a period of time. EGFRdel19/T790M/C797S and EGFRL858R/T790M/C797S are two most prevalent tertiary EGFR mutants identified in Osimertinib-resistant tumors and currently there is no therapy approved clinically targeting these mutants. In this study, we designed and synthesized a series of novel 4th generation EGFR inhibitors based on scaffold of Brigatinib. After extensive SAR studies, compound 23, the most promising candidate, exhibited strong biochemical potencies against EGFRdel19/T790M/C797S, EGFRL858R/T790M/C797S and other clinically relevant EGFR mutants while sparing wild type EGFR. In cellular assays, compound 23 potently inhibited proliferation of BaF3EGFR del19/T790M/C797S and PC-9EGFR del19/T790M/C797S. Moreover, compound 23 demonstrated good DMPK profile in mouse PK study.

Research on sand body architecture at the intersection of a bidirectional sedimentary system in the Jiyuan area of Ordos Basin.

The exploration and development of the dual-provenance lower assemblage of the Yanchang Formation in the Jiyuan area has progressed rapidly. At the intersection of this bidirectional provenance system, a complex and variable spatial combination of sand bodies formed, resulting in significant structural heterogeneity in the development and distribution of reservoirs. Based on previous studies, this paper combines core data and logging data with a large number of analytical tests and production performance data to carry out research on the Chang 82-Chang 9 reservoir group in the lower assemblage of the Yanchang Formation in the Shijiawan-Buziwan area. Based on the analysis of sedimentary conditions, the sand body development pattern at the intersection of the bidirectional sedimentary system in the study area was analysed by stepwise dissection of the sand body architecture. After the types and characteristics of the 4th- to 5th-level architectural elements were determined, the spatial distribution of the combinations of these elements was assessed and combined with logging discriminant analysis and geometric shape prediction methods to identify a 'prism' architectural distribution pattern. The architectural elements are connected with the distribution of diagenetic facies, the spatial distribution patterns of different types of diagenetic facies under the constraints of the architecture are summarized by region, and the locations of potential favourable reservoir development are discussed. The results show that the degree of superposition and combination of the eight skeletal architectural elements in the target layers gradually deteriorate from the bottom to the top. In addition, the development scale and degree of architectural elements in the braided river delta system in the west are better than those in the meandering river delta system in the east. In the different sedimentary areas, the spatial combination styles of the architectural elements are quite different, and the combination of these elements gradually changes from a combination of braided channels (FA1) and abandoned channels (FA2) to a combination of underwater distributary channels (FA4). Matching of the distribution of diagenetic facies with the distribution of architectural elements reveals that the diagenetic facies dominated by intergranular pores and dissolution pores (associated with good reservoir physical properties) are usually found at the bottom or in the lower to middle parts of the skeletal architectural elements.