Discovery of 4,5-dihydro-benzo[g]indazole-based hydroxamic acids as HDAC3/BRD4 dual inhibitors and anti-tumor agents.

Concurrent inhibition of HDAC and BRD4, two well-established epigenetic targets for anti-tumor therapy, demonstrates the potential to enhance anti-tumor effects synergistically. The present study involves the development of a series of novel HDAC3/BRD4 dual inhibitors, followed by evaluation of their antitumor efficacy against several tumor models. Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor 17h.

Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.

Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported.

Unlocking the potential: advancements and future horizons in ROR1-targeted cancer therapies.

While receptor tyrosine kinase-like orphan receptor 1 (ROR1) is typically expressed at low levels or absent in normal tissues, its expression is notably elevated in various malignant tumors and conditions, including chronic lymphocytic leukemia (CLL), breast cancer, ovarian cancer, melanoma, and lung adenocarcinoma. This distinctive feature positions ROR1 as an attractive target for tumor-specific treatments. Currently, several targeted drugs directed at ROR1 are undergoing clinical development, including monoclonal antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell therapy (CAR-T).

Discovery of Novel Mcl-1 Inhibitors with a 3-Substituted-1-indole-1-yl Moiety Binding to the P1-P3 Pockets to Induce Apoptosis in Acute Myeloid Leukemia Cells.

Mcl-1 is a main antiapoptotic protein in acute myeloid leukemia (AML) and is used as a target to develop inhibitors. Currently, potent Mcl-1 inhibitors primarily interact with the P2-P4 pockets of Mcl-1, but pharmacological modulation by targeting the P1 pocket is less explored. We designed a series of 1-indole-2-carboxylic acid compounds as novel Mcl-1 inhibitors occupying the P1-P3 pockets and evaluated their Mcl-1 inhibition and apoptosis induction in AML cells.

Characterization and noncovalent inhibition of the K63-deubiquitinase activity of SARS-cov-2 PLpro.

SARS-CoV-2 papain-like protease (PLpro) could facilitate viral replication and host immune evasion by respectively hydrolyzing viral polyprotein and host ubiquitin conjugates, thereby rendering itself as an important antiviral target. Yet few noncovalent PLpro inhibitors of SARS-CoV-2 have been reported with improved directed towards pathogenic deubiquitinating activities inhibition. Herein, we report that coronavirus PLpro proteases have distinctive substrate bias and are conserved to deubiquitylate K63-linked polyubiquitination, thereby attenuating host type I interferon response.

Directly targeting BAX for drug discovery: Therapeutic opportunities and challenges.

For over two decades, the development of B-cell lymphoma-2 (Bcl-2) family therapeutics has primarily focused on anti-apoptotic proteins, resulting in the first-in-class drugs called BH3 mimetics, especially for Bcl-2 inhibitor Venetoclax. The pro-apoptotic protein Bcl-2-associated X protein (BAX) plays a crucial role as the executioner protein of the mitochondrial regulated cell death, contributing to organismal development, tissue homeostasis, and immunity. The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death, such as cancer, neurodegeneration, and heart failure.

Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors.

The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting Mnk kinases is a promising approach for cancer therapy. Starting with fragment WS23, a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound 15b showed the highest potency with IC values of 0.

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions.

As a tripartite cell death switch, B-cell lymphoma protein 2 (Bcl-2) family members precisely regulate the endogenous apoptosis pathway in response to various cell signal stresses through protein-protein interactions. Myeloid leukemia-1 (Mcl-1), a key anti-apoptotic Bcl-2 family member, is positioned downstream in the endogenous apoptotic pathway and plays a central role in regulating mitochondrial function. Mcl-1 is highly expressed in a variety of hematological malignancies and solid tumors, contributing to tumorigenesis, poor prognosis, and chemoresistance, making it an attractive target for cancer treatment.

Optimization of the synthesis of BET BD2 selective inhibitor XY153.

XY153 is a promising BET BD2 inhibitor with an IC value of 0.79 nM against BRD4 BD2. It shows 354-fold selectivity over BRD4-BD1 and 6-fold selectivity over other BET BD2 domains.

Construction of Diversified Penta-Spiro-Heterocyclic and Fused-Heterocyclic Frameworks with Potent Antitumor Activity.

Invited for the cover of this issue are Xuewu Liang, Hong Liu and co-workers at the Shanghai Institute of Materia Medica and Shenyang Pharmaceutical University. The image depicts how a rhodium-catalyzed methodology leads to novel penta-spiro/fused-heterocyclic frameworks with potent antitumor activity through C-H activation/[4+1] and [4+2] annulation cascades. Read the full text of the article at 10.

Computer-aided drug design course for pharmacy major students in Shenyang Pharmaceutical University following the COVID-19 pandemic: Challenges and opportunities.

The computer-aided drug design (CADD) course that spans biochemistry, computational chemistry, medicinal chemistry, and other cutting-edge sciences is considered an important course by pharmaceutical universities in China. The course teaches students how drugs bind to protein targets and exert their biological activities using computer tools, and covers the basic principles of drug development and optimization. Due to the lockdown and social distancing measures adopted during the coronavirus disease 2019 (COVID-19) pandemic, the CADD course in Shenyang Pharmaceutical University was briefly suspended.

Construction of Diversified Penta-Spiro-Heterocyclic and Fused-Heterocyclic Frameworks with Potent Antitumor Activity.

Multiple-spiro/fused-heterocyclic frameworks containing indazolone are structurally unique and represent a class of potentially dominant skeletons. In this work, we successfully fulfilled Rh(III)-catalyst mediated substrate- and pH- controlled strategies to construct four novel types of complicated penta-spiro/fused-heterocyclic frameworks via C-H activation/[4+1] and [4+2] annulation cascades. This method had mild reaction conditions, a broad scope of substrates, moderate to good yields, and valuable applications, which could realize for the first time the generation of the novel di-spiro-heterocyclic and multiple fused-heterocyclic products with unique structures.

Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer.

Multivalency is an attractive strategy for effective binding to target protein. Bromodomain and extra-terminal (BET) family features two tandem bromodomains (BD1, BD2), which are considered to be potential new targets for prostate cancer. Herein, we report the rational design, optimization, and evaluation of a class of novel BET bivalent inhibitors based on our monovalent BET inhibitor 7 (Y06037).

Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties.

Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis.

Synthesis of Paclitaxel Derivatives for Remote Loading into Liposomes and Improved Therapeutic Effect.

A series of novel paclitaxel derivatives modified by boronic acid according to the characteristics of the interaction between RB(OH)2 and different strapping agents of intraliposomal aqueous phase were designed and synthesized, which were then used to develop remote poorly water-soluble drugs loading into liposomes. Meanwhile, we screened nineteen paclitaxel boronic acid derivatives for their cytotoxic activities against three cancer cell lines (A549, HCT-116 and 4T1) and one normal cell line (LO2), and performed liposome formulation screening of active compounds. Among all the compounds, the liposome of 4d, with excellent drug-encapsulated efficiency (>95% for drug-to-lipid ratio of 0.

Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety.

The B cell lymphoma protein 2 (Bcl-2) family proteins regulate cell apoptosis by participating in the endogenous apoptosis pathway. As an important anti-apoptotic protein, Myeloid cell leukemia 1 (Mcl-1) is overexpressed in a variety of tumor cells, and targeting this protein has been a promising strategy for cancer therapy. Herein, based on the 1H-indole-5-carboxylic acid structure previously discovered, we have developed a series of novel compounds with increased affinities and selectivity toward Mcl-1 through structure-based drug design.

Discovery and structure-activity relationship studies of novel Bcl-2/Mcl-1 dual inhibitors with indole scaffold.

The Bcl-2 anti-apoptotic proteins were widely overexpressed in diverse tumor cells, especially for Bcl-2 and Mcl-1, which regarding as important targets of apoptosis induction and resistance of chemotherapy. We identified novel Bcl-2/Mcl-1 dual inhibitors with indole scaffold by the optimization of hit 1. Structure modification against several moieties including hydrophobic fragment, side chain and benzoic acid fragment was conducted and the structure-activity relationship was analyzed.

Artesunate improves venetoclax plus cytarabine AML cell targeting by regulating the Noxa/Bim/Mcl-1/p-Chk1 axis.

Venetoclax plus cytarabine therapy is approved for elderly acute myeloid leukemia (AML) patients and needs further improvement. We studied the mechanisms of venetoclax plus cytarabine treatment and searched for a third agent to enhance their effects. Cytarabine induces S phase arrest-mediated DNA damage with activation of DNA replication checkpoint kinase 1 (Chk1) through phosphorylation, while venetoclax induces B cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim)-mediated apoptotic DNA damage.

Trends in targeting Bcl-2 anti-apoptotic proteins for cancer treatment.

Apoptosis is the major mode of programmed cell death, which conduces to maintain tissue homeostasis, clearance of abnormal cells and development of organisms. Over the past two decades, great progress and significant clinical benefits in cancer treatment have been made by targeting Bcl-2 anti-apoptotic proteins. However, with the deep research of clinic, the therapeutic value of single target inhibitors is restricted due to the limited monotherapy activity, potential and complex drug resistance as well as monotherapy safety.

Small molecules targeting γ-secretase and their potential biological applications.

The γ-secretase is a large transmembrane protein complex composed of four distinct units. It has aroused numerous attention over the past two decades as its intriguing role in mediating intramembrane proteolysis. γ-Secretase controls the cleavage of a broad ranged substrates, part of which have implicated in the pathogenesis of Alzheimer's disease, inflammation, and tumorigenesis.

Discovery of Novel Indole Derivatives as Fructose-1,6-bisphosphatase Inhibitors and X-ray Cocrystal Structures Analysis.

Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis, and its inhibitors are expected to be novel antidiabetic agents. Herein, a series of new indole and benzofuran analogues were designed and synthesized to evaluate the inhibitory activity against FBPase. As a result, the novel FBPase inhibitors bearing -acylsulfonamide moiety on the 3-position of the indole-2-carboxylic acid scaffold (compounds and ) were identified with ICs at the submicromolar levels.

Optimization of 4,6-Disubstituted Pyrido[3,2-]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth.

Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed.

Design, synthesis and biological evaluation of dual Bcl-2/Mcl-1 inhibitors bearing 2-(1H-indol-4-yl)benzoic acid scaffold.

The anti-apoptotic protein inhibitors of the B cell lymphoma 2 (Bcl-2) family have been developed as new anticancer therapies. Numerous studies illustrated the great potential in the development of dual Bcl-2/myeloid cell leukemia 1 (Mcl-1) inhibitors. Herein, we reported a series of Bcl-2/Mcl-1 inhibitors that optimized from a hit compound 1 via structure-based rational design.

Design, synthesis and biological evaluation of selective histone deacetylase 6 (HDAC6) inhibitors bearing benzoindazole or pyrazoloindazole scaffold as surface recognition motif.

A series of compounds were designed and synthesized based on the compound 11i bearing phenylpyrazole scaffold with histone deacetylase 6 (HDAC6) inhibitory activity. Most of the compounds showed considerable inhibitory activity against HDAC6 and compound A16 with good inhibitory activity was found therein. We further found that A16 had an inhibitory effect on inflammatory mediators (NO, TNF-α, IL-6) involved in inflammatory response and neuroendocrine regulation.