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Structural simplification: an efficient strategy in lead optimization

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Acta Pharmaceutica Sinica B 2019年第5期9卷 880-901页

作者： shengzheng Wang Guoqiang Dong chunquan sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai200433China Department of Medicinal Chemistry and Pharmaceutical Analysis School of PharmacyFourth Military MedicalUniversityXi’an710032China

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding 'molecular obesity'. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

关键词： Structural simplification Lead optimization Drug discovery Drug design Reducing rings number Reducing chiral centers Structure-based simplification Pharmacophore-based simplification

Small molecules for combating multidrug-resistant superbug Candida auris infections

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4056-4074页

作者： Jie Tu Na Liu Yahui Huang Wanzhen Yang chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

关键词： Candidaauris Antifungal agents Drug resistance Virulence factors Antifungal targets

RMC-7977,a highly selective inhibitor of the active RAS-GTP to treat pancreatic cancer

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4622-4624页

作者： Ying-Qi Song Qingjun Li chunquan sheng Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570228China The Center for Basic Research and Innovation of Medicine and Pharmacy(MOE) School of PharmacySecond Military Medical University(Naval Medical University)Shanghai 200433China

Recently,a novel research led by Mallika Singh and Kenneth ***^(1,2) published in Nature identified a highly selective inhibitor(RMC-7977)of the active GTP-bound forms of human RAS family(KRAS,HRAS and NRAS)with affinity for both mutant and wild-type ***,they assessed the therapeutic potential of RMC-7977 in a comprehensive range of human pancreatic ductal adenocarcinoma(PDAC)models and proved that RMC-7977 could induce apoptosis and sustained proliferative arrest,whereas normal tissues underwent only transient decreases in ***.

关键词： RMC-7977 RAS-GTP Inhibitor Pancreatic cancer

Evodiamine-inspired dual inhibitors of histone deacetylase 1(HDAC1) and topoisomerase 2(TOP2) with potent antitumor activity

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Acta Pharmaceutica Sinica B 2020年第7期10卷 1294-1308页

作者： Yahui Huang Shuqiang Chen Shanchao Wu Guoqiang Dong chunquan sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug *** by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor ***,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their *** together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

关键词： Evodiamine Histone deacetylase Topoisomerase Dual inhibitors Antitumor activity

Constructing virtual combinatorial fragment libraries based upon MDL Drug Data Report database

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Science China Chemistry 2007年第3期50卷 364-371页

作者： ZHANG Min sheng chunquan XU Hui SONG YunLong ZHANG WanNian School of Pharmacy Second Military Medical UniversityShanghai 200433China

Structural analysis of known drugs or drug-like compounds provides important information for drug design. The 142553 drug molecules in the MDL Drug Data Report database were analyzed, and then the common structural features were extracted. According to the common structural features, drug molecules were segmented into 32017 fragments, including 13642 ring fragments, 10076 linker fragments, and 8299 side chain fragments. These fragments were further used to establish three types of virtual combinatorial fragment libraries: a basic framework library containing 13574 rings; a linker library of 8051 linkers and a pharmacophore library of 34244 fragments combined by rings and side chains. After energy minimization, all fragments in the above three libraries maintain reasonable geometrical features and spatial conformations, and would be useful for building a virtual combinatorial database and de novo drug design.

关键词： drug design fragment molecular database statistical analysis drug molecule

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2859-2868页

作者： Ying Wu Congying Pu Yixian Fu Guoqiang Dong Min Huang chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 201203China

Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and ***,therapeutic benefit of NAMPT enzymatic inhibitors appears very limited,likely due to the failure to intervene nonenzymatic functions of ***,we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells(MDSCs) via a mechanism independent of its enzymatic *** proteolysis-targeting chimera(PROTAC) technology,PROTAC A7 is identified as a potent and selective degrader of NAMPT,which degrades intracellular NAMPT(iNAMPT) via the ubiquitin-proteasome system,and in turn decreases the secretion of extracellular NAMPT(eNAMPT),the major player of the non-enzymatic activity of *** vivo,PROTAC A7 efficiently degrades NAMPT,inhibits tumor infiltrating MDSCs,and boosts antitumor *** note,the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on ***,our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment,and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT,pointing out a new direction for the development of NAMPT-targeted therapies.

关键词： NAMPT Non-enzymatic function eNAMPT Cancer MDSC PROTAC Tumor immunity Immunotherapy

Asymmetric Synthesis, Antifungal Activity and Molecular Modeling of Iodiconazole Isomers

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Chinese Journal of Chemistry 2013年第9期31卷 1139-1143页

作者： Yongqiang Zhang shengzheng Wang Zhenyuan Miao Jianzhong Yao Wannian Zhang chunquan sheng Department of Medicinal Chemistry School of Pharmacy Second Military Medical University Shanghai 200433 China

Iodiconazole is a novel antifungal agent that was developed in its racemic form. In order to investigate the ef- fects of the chiral center on the antifungal activity, R- and S-isomers of iodiconazole were prepared on the basis of the asymmetric Sharpless epoxidation. （S）-Iodiconazole was proved to have better antifungal activity than the （R）- isomer. The binding modes of the two isomers with lanosterol 14~z-demethylase were clarified by molecular dock- ing.

关键词： iodiconazole asymmetric synthesis optically pure isomers antifungal activity molecular docking

Hydrophobic tagging-induced degradation of NAMPT in leukemia cells

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Chinese Chemical Letters 2024年第9期35卷 214-218页

作者： Menglu Guo Ying-Qi Song Junfei Cheng Guoqiang Dong Xun Sun chunquan sheng Department of Natural Medicine School of PharmacyFudan UniversityShanghai 201203China School of Pharmaceutical Sciences Hainan UniversityHaikou 570228China School of Pharmacy Second Military Medical UniversityShanghai 200433China

Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer *** the therapeutic potential of NAMPT enzymatic inhibitors,their effectiveness is limited by dose-related toxicity and the inability to suppress nonenzymatic functions of extracellular NAMPT(e NAMPT).Herein,we designed and synthesized the first hydrophobic tagging NAMPT *** them,compound NH-11 selectively degraded NAMPT in leukemia cells through the ubiquitin-proteasome *** NH-11 effectively induced apoptosis and showed low toxicity to normal cells,representing a promising anti-leukemia lead compound.?2024 Published by Elsevier *** behalf of Chinese Chemical Society and Institute of Materia Medica,Chinese Academy of Medical Sciences.

关键词： NAMPT Hydrophobic tagging Leukemia Degradation Anti-cancer

Controlling antifungal activity with light:Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

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Acta Pharmaceutica Sinica B 2023年第7期13卷 3080-3092页

作者： Zhuang Li Na Liu Wanzhen Yang Jie Tu Yahui Huang Wei Wang chunquan sheng State Key Laboratory of Bioengineering Reactor And Shanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science&TechnologyShanghai 200237China School of Pharmacy Second Military Medical University(Naval Medical University)Shanghai 200433China Department of Pharmacology and Toxicology College of PharmacyAnd BIO5 InstituteUniversity of ArizonaTucsonAZ 85721USA

Invasive fungal infections(IFIs)have been associated with high mortality,highlighting the urgent need for developing novel antifungal *** the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14a-demethylase(CYP51)*** photocaged triazoles completely shielded the *** content of ergosterol in fungi before photoactivation and after photoactivation was 4.4%and 83.7%,***,the shielded antifungal activity(MIC80≥64μg/m L)could be efficiently recovered(MIC80=0.5—8μg/m L)by light *** new chemical tools enable optical control of fungal growth arrest,morphological conversion and biofilm *** ability for highprecision antifungal treatment was validated by in vivo *** light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection ***,this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

关键词： Antifungal agents Ergosterol biosynthesis Triazoles Photocaged Optical control