Protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation which affects a myriad of cellular processes. Imbalance in signal pathways mediated by PTPs has been associated with development of many human diseases including cancer, metabolic, and immunological diseases. Several compelling evidence suggest that many members of PTP family are novel therapeutic targets. However, the clinical development of conventional PTP-based active-site inhibitors originally was hampered by the poor selectivity and pharmacokinetic properties. In this regard, PTPs has been widely dismissed as "undruggable." Nonetheless, allosteric modulation has become increasingly an influential and alternative approach that can be exploited for drug development against PTPs. Unlike active-site inhibitors, allosteric inhibitors exhibit a remarkable targetselectivity, drug-likeness, potency, and in vivo activity. Intriguingly, there has been a high interest in novel allosteric PTPs inhibitors within the last years. In this review, we focus on the recent advances of allosteric inhibitors that have been explored in drug discovery and have shown an excellent result in the development of PTPs-based therapeutics. A special emphasis is placed on the structure-activity relationship and molecular

Encoded by PTPN11 , the SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is widely recognized as a carcinogenic phosphatase. As a promising anti-cancer drug target, SHP2 regulates many signaling pathways such as RAS-RAF-ERK, PI3K-AKT and JAK-STAT. Meanwhile, SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment. Heretofore, five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer. Most recently, studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1 (PD-1) blockade. Herein, we review the structure, function and small molecular inhibitors of SHP2, and highlight recent progress in overcoming drug resistance using SHP2 inhibitor. We hope this review would facilitate the future clinical development of SHP2 inhibitors.

: The PROTAC (PROteolysis TArgeting Chimera) technology is a target protein degradation strategy, based on the ubiquitin-proteasome system, which has been gradually developed into a potential means of targeted cancer therapy in recent years. This strategy has already shown significant advantages over traditional small-molecule inhibitors in terms of pharmacodynamics, selectivity, and drug resistance. Several small molecule PROTACs have been in a Phase I clinical trial. Herein, we introduced the mechanism, characteristics, and advantages of PROTAC strategy. And we summarize the recent advances in the development of small-molecule PROTACs for cancer treatment. We hope this review will be helpful in optimizing the design of the ideal small-molecule PROTACs and advancing targeted anticancer research.

Introduction: Cryptococcosis is a ubiquitous opportunistic fungal disease caused by Cryptococcus neoformans var. grubii. It has high global morbidity and mortality among HIV patients and none-HIV carriers with 99% and 95% respectively. Furthermore, the increasing prevalence of undesired toxicity profile of antifungal, multi-drug resistant organism, and the scarcity of FDA authorized vaccines, where the hallmark in the present days. This study was undertaken to design a reliable multi-epitope peptide vaccine against highly conserved immunodominant heat shock 70KDa protein of Cryptococcus neoformans var. grubii that covers a considerable digit of the world population through implementing computational vaccinology approach. Materials and Methods: A total of 38 Sequences of Cryptococcus neoformans var. grubii's heat shock 70KDa protein were retrieved from NCBI protein database. Different prediction tools were used to analyze the aforementioned protein at Immune Epitope Database (IEDB) to discriminate the most promising Tcell and B-cell epitopes. Then the proposed epitopes were subjected to Population coverage analysis tool to compute global population's coverage. Finally, the projected epitopes were ranked based on their scores and binding modes through using Moe 2007 program. Outstanding Results and Conclusion: Our prime vaccine candidate was a putative ten promising epitopes (ANYVQASEK, NYVQASEK, KSVEKPAS, TPQQPPAQ, YVYDTRGKL, FYRQGAFEL, FTQLVAAYL, FFGGKVLNF, FDYALVQHF, and FINAQLVDV). Together, these epitopes are forecasted to trigger T lymphocytes, B lymphocytes, and immunological memory with overall population coverage above 90%. Accordingly, our in silico vaccine is expected to be the future multi-epitope peptide vaccine against Cryptococcus neoformans var. grubii's heat shock 70KDa protein that covers a significant figure of the entire world citizens. Therefore, there is a definite need for experimental validation for the carefully chosen vaccine candidates in vitro and in vivo to fortify their antigenic and immunogenic potentials. Additionally, further computational studies are needed to be conducted in pathogens-derived Heat shock 70KDa protein family, as it believed to find universal epitopes that might be overlapped with other pathogens-derived Hsp70.Keywords: Multi-epitope peptide vaccine, Computational vaccinology, Cryptococcus neoformans var. grubii, Cryptococcosis, in silico vaccine, Heat shock 70KDa protein (Hsp70).

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Inspired by the synergistic effect of BTSA1 (a Bax activator) and SAHA (a histone deacetylase (HDAC) inhibitor) in HeLa cell growth suppression, a series of novel HDAC–Bax multiple ligands were designed rationally. Compound 23, which possesses similar HDAC inhibitory activity relative to SAHA and Bax affinity comparable to BTSA1, exhibits a superior growth suppression against HeLa cells, and its antiproliferative activities are 15-fold and 3-fold higher than BTSA1 and SAHA, respectively. The better antiproliferative activity and lower cytotoxicity of compound 23 indicated that our HDAC–Bax multiple ligand design strategy achieved success. Further studies suggested that compound 23 could enhance Bax-dependent apoptosis by upregulating Bax, followed by inducing the conformational activation of Bax. To our knowledge, we first report HDAC–Bax multiple ligands and demonstrate a new paradigm for the treatment of solid tumors by enhancing Bax-dependent apoptosis.

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