From bench to bedside: current development and emerging trend of KRAS-targeted therapy

SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling. SHP2 may be inhibited by molecules that cause allosteric (bind to sites other than the active site and attenuate activation) or orthosteric (bind to the active site and stop activation) inhibition or via potent SHP2 degraders. These inhibitors have anti-proliferative effects in cancer cells and suppress tumor growth in preclinical models. In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

In this study, a 4H-SiC homoepitaxial layer was grown on a 150 mm 4° off-axis substrate using a horizontal hot wall chemical vapor deposition reactor. Comparing C3H8 and C2H4 as C sources, the sample grown with C2H4 exhibited a slower growth rate and lower doping concentration, but superior uniformity and surface roughness compared to the C3H8-grown sample. Hence, C2H4 is deemed more suitable for commercial epitaxial wafer growth. Increasing growth pressure led to decreased growth rate, worsened thickness uniformity, reduced doping concentration, deteriorated uniformity, and initially improved and then worsened surface roughness. Optimal growth quality was observed at a lower growth pressure of 40 Torr. Furthermore, the impact of buffer layer growth on epitaxial quality varied significantly based on different C/Si ratios, emphasizing the importance of selecting the appropriate conditions for subsequent device manufacturing.

Research on the Influence of Carbon Sources and Buffer Layers on the Homogeneous Epitaxial Growth of 4H-SiC

Analysis of thermal cavitation in a viscoelastic composite sphere under a uniform temperature field

Although the SiC MOSFETs with square or hexagonal designed cells have a small on-resistance, the electric fields of sharp corners within these designed cells lead to the reduction of blocking voltage. The SiC MOSFETs with linear cells can maintain the blocking voltage, while the relatively large cell usually increases the on-resistance and power consumption. In this article, we designed and fabricated the SiC MOSFETs with linear cells and interrupted linear cells whose N+ region is embedded with the P+ region. Then we compare their characteristics of specific on-resistance, forward characteristic, and blocking voltage, and report the demonstration of a high-voltage 4H-silicon carbide (SiC) MOSFETs with 20% losses of on-resistance by interrupting the N+ region with P+ region. We provide a new linear cell design that can effectively reduce the on-resistance of 1200 V SiC MOSFET and maintain the blocking voltage.

Implementation of 1200V SiC MOSFET with 20% Lower On-Resistance by Designing the Interrupted P+ Region


 Src homology region 2 domain-containing phosphatase-2 (SHP-2) is a key node in the RAS signaling pathway. Allosteric inhibition of SHP2 phosphatase is a potential therapeutic strategy for cancers harboring oncogenic mutations in the KRAS pathway. SHP2 also participates in the signal transduction downstream of regulatory immunoreceptors, and it has been shown in preclinical models that SHP2 inhibition drives anti-tumor immunity through modulation of both innate and adaptive mechanism. BPI-442096 is a potent, selective, and orally bioavailable small molecule SHP2 inhibitor. It exhibited significant anti-proliferation activities against multiple KRAS mutant cancer cell lines, including those from NSCLC, PDAC, CRPC, etc. BPI-442096 dose-dependently inhibited SHP2 phosphatase and downstream ERK phosphorylation in cancer cells, as well as NFAT reporter gene expression downstream of PD-1/PD-L1 signaling in immune cells. In vivo, BPI-442096 demonstrated strong tumor growth inhibition in KRASG12C, KRASG12D, and KRASG12V mutant xenograft mouse models. BPI-442096 also exhibited anti-tumor immunity in the MC38 syngeneic model, as a single agent or in combination with anti-PD1/PD-L1 drugs. Moreover, BPI-442096 combining with KRASG12C inhibitor may reverse intrinsic and acquired resistance to KRASG12C inhibition. Adequate oral exposure across multiple pre-clinical species and good ADME properties ensured the druggability of BPI-442096. In conclusion, BPI-442096 exhibits a robust anti-tumor effect in multiple KRAS mutant models and enhanced anti-cancer immunity in syngeneic mouse models, and it shows multiple combination potentials to overcome drug resistance. Phase 1 clinical trial is planned in early 2022.
 Citation Format: Ling Li, Bang Fu, Han Han, Zhongxin Sun, Xiangdong Zhao, Xuepeng Jv, Jun Tong, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Wei Ren, Yinlong Li, Wenmao Wu, Jing Guo, Dan Yan, Xiangyong Liu, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5463.

Abstract 5463: BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers

Characterization of 1.2kV 4H-SiC Planar Power MOSFETs

Effects of Constant Voltage Stress on Bipolar Degradation in 4H-SiC IGBT

Abstract The microvoid growth in an infinite medium under thermal shock was analyzed on the basis of the viscoelastoplastic theory. In the mathematical model of the problem, the stage of purely viscoelastic deformation was taken into account. The direct integration method is used to find the analytical expressions of displacement and stress. The moving interface between the viscoelastic and the viscoplastic zones was involved, and its location was determined by the nonlinear ordinary differential equation with initial condition. As an example, the evolution of void with time for the aluminum alloy material was investigated by numerical computation. The effects of the temperature variation, the heating rate, and the viscosity of material on the void growth were examined. The analysis indicated that the relationship between void growth and temperature load is nonlinear due to the appearance of moving interface.

Dynamic analysis on microvoid growth in viscoelastoplastic materials under thermal shock

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Abstract 5463: BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers

Characterization of 1.2kV 4H-SiC Planar Power MOSFETs

Effects of Constant Voltage Stress on Bipolar Degradation in 4H-SiC IGBT

Dynamic analysis on microvoid growth in viscoelastoplastic materials under thermal shock