Selectivity Comparison of Tumor-Imaging Probes Designed Based on Various Tumor-Targeting Strategies: A Proof of Concept Study.

Fluorescence probes are emerging as appealing tools for tumor imaging, although the discovery of ideal probes with high tumor selectivity and desirable tumor-to-normal contrast remains challenging. There are currently two strategies used for designing tumor-targeted probes. One is employing tumor-targeting agents and the other is tumor-microenvironment-activatable probes.

Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation.

Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening.

Discovery of -((3,4)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity.

Rash is one of the primary dose-limiting toxicities of Akt (protein kinase B) inhibitors in clinical trials. Here, we demonstrate the inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis, which promotes us to search for new selective Akt inhibitors with an improved cutaneous safety property. According to our previous research, compound is selected for further optimization for overcoming the disadvantages of compound , including high Akt2 inhibition and high toxicity against HaCaT keratinocytes.

Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis.

The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis.

Discovery of 1,5-Dihydro-4-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2.

CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2) have been demonstrated to have critical roles in cancer metastasis. Because they share high homology sequences, it is still unclear how to design selective CXCR1 or CXCR2 antagonists. Based on a pharmacophore model we built, compound bearing a 1,5-dihydro-4-imidazol-4-one scaffold was identified as a selective CXCR2 antagonist with a low CXCR1 antagonism preference.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent.

Identification of N-phenyl-3-methoxy-4-pyridinones as orally bioavailable H receptor antagonists and β-amyloid aggregation inhibitors for the treatment of Alzheimer's disease.

Based on our previous work, a series of N-phenyl-3-methoxy-4-pyridinone derivatives were designed as orally bioavailable dual functional agents for therapy of Alzheimer's disease, through introducing alkyloxy moiety into 4-pyridinone ring to avoid the possible phase II metabolism of 3-hydroxy-4-pyridinone in lead compound 3-hydroxy-2-methyl-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (4). In vitro studies indicated that most of these compounds exhibit excellent H receptor antagonistic activities and potent self-induced Aβ/Aβ aggregation inhibitory activities. In particular, 3-methoxy-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (7i) demonstrated IC value of 0.

An inherently kidney-targeting near-infrared fluorophore based probe for early detection of acute kidney injury.

Acute kidney injury (AKI) is common in hospital patients. Delayed diagnosis and treatment of AKI due to the lack of efficient early diagnosis is an important cause of its high mortality. While fluorescence imaging seems promising to non-intrusively interrogate AKI-related biomarkers, the low kidney contrast of many fluorophores conferred by their relatively low abundance of distribution in the kidney limits their application for AKI detection.

Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells.

The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes.

Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation.

Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib.

A fluorogenic probe for tracking GSH flux in developing neurons.

Understanding GSH flux in developing neurons is prerequisite to reveal its role in neuronal development but necessiates an ultrasensitive assay. By systematically exploring key structural factors determing probe sensitivity in live cells, we developed a fluorogenic probe capable of imaging subtle GSH fluctuations in developing neurons.

Microenvironment-Responsive Small-Molecule Probe for Pulmonary Fibrosis Detection.

Pulmonary fibrosis (PF) is a fatal disease with increasing prevalence. Nonradioactive and noninvasive diagnosis of PF at an early stage can improve the prognosis but represents a daunting challenge. Up-regulation of nitric oxide (NO) is a typical microenvironmental feature of PF.

Physicochemical-property guided design of a highly sensitive probe to image nitrosative stress in the pathology of stroke.

real-time imaging of nitrosative stress in the pathology of stroke has long been a formidable challenge due to both the presence of the blood-brain barrier (BBB) and the elusive nature of reactive nitrogen species, while this task is also informative to gain a molecular level understanding of neurovascular injury caused by nitrosative stress during the stroke episode. Herein, using a physicochemical property-guided probe design strategy in combination with the reaction-based probe design rationale, we have developed an ultrasensitive probe for imaging nitrosative stress evolved in the pathology of stroke. This probe demonstrates an almost zero background fluorescence signal but a maximum 1000-fold fluorescence enhancement in response to peroxynitrite, the nitrosative stress marker.

Design, synthesis, and biological study of 4-[(2-nitroimidazole-1-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia.

Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.

Methods: A series of 4-[(2-nitroimidazole-1-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound.

Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors.

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic cancer cells and their potential of inducing apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development.

Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design.

A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, , that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound , involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative . showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles.

GSH Activated Biotin-tagged Near-Infrared Probe for Efficient Cancer Imaging.

Tumor imaging tools with high specificity and sensitivity are needed to aid the boundary recognition in solid tumor diagnosis and surgical resection. In this study, we developed a near infra-red (NIR) probe () for tumor imaging on the basis of the dual strategy of cancer cell targeting and stimulus-dependent activation. The selective imaging capacity towards cancer cells of was thoroughly investigated, and the potential mechanisms of endocytosis were preliminary explored.

Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies.

Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC of 0.

Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies.

A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC values against PI3Kδ and submicromolar GI values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers.

Phenotypic Screening-Based Identification of 3,4-Disubstituted Piperidine Derivatives as Macrophage M2 Polarization Modulators: An Opportunity for Treating Multiple Sclerosis.

Multiple sclerosis (MS) is a disease of the autoimmune-mediated disorder in the central nervous system, for which no effective therapeutic agent is currently available. The regulation of macrophage polarization toward M2 is a general benefit for treating MS. The gene biomarker-based phenotypic screening approach was developed, and 3,4-disubstituted piperidine derivative S-28 was identified as a lead compound modulating macrophage M2 polarization.

Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles.

The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event.

Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors.

Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors, 30 oprozomib-derived macrocyclic peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure-activity relationship (SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration.

Ligand-based pharmacophore model for the discovery of novel CXCR2 antagonists as anti-cancer metastatic agents.

Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with the HipHop program by screening a database containing compounds which were designed based on the known structure-activity relationship (SAR) of the diarylurea series CXCR2 antagonists.

Integrating docking scores and key interaction profiles to improve the accuracy of molecular docking: towards novel B-Raf inhibitors.

A set of ninety-eight B-Raf inhibitors was used for the development of a molecular docking based QSAR model using linear and non-linear regression models. The integration of docking scores and key interaction profiles significantly improved the accuracy of the QSAR models, providing reasonable statistical parameters ( = 0.935, = 0.