Xin Huang

The Second Xiangya Hospital of Central South University, Ch’ang-sha-shih, Hunan, China

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Publications (45)149.35 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogs. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent anti-tumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts towards the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
    Journal of Medicinal Chemistry 03/2014; · 5.61 Impact Factor
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    ABSTRACT: We previously reported the discovery of AMG 232 (2), a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse inhibitors led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and the metabolic stability compared to their piperidinone counterparts. Within this morpholinone series, AM-8735 (4) emerged as a potent inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 22 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent anti-tumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization towards the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
    Journal of Medicinal Chemistry 02/2014; · 5.61 Impact Factor
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    ABSTRACT: We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo anti-tumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
    Journal of Medicinal Chemistry 01/2014; · 5.61 Impact Factor
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    ABSTRACT: Tankyrases (TNKS1 and TNKS2) are proteins in the poly-ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting -catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was previously identified as an inhibitor of tankyrase through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
    Journal of Medicinal Chemistry 12/2013; · 5.61 Impact Factor
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    ABSTRACT: Objective: To explore the relationship between prenatal anxiety and cesarean section (c-section) with non-medical indication. Methods: Nested case-control study was used to analyze the risk factors for c-section with no medical needs: 433 pregnant women with gestational age longer than 24 weeks were enrolled in this study. According to the mode of delivery, we divided them into a vaginal delivery group, a c-section group without medical need and a c-section group with medical need. Results: The c-section rate was 62.1%, 55.8% of which was c-section without medical need at family request. The score of state anxiety (S-AI) and trait anxiety (T-AI) was 42.53±11.04 and 44.40±10.23 respectively, much higher than that of normal population. After the adjustment of maternal social economic status and other prenatal statuses for this pregnancy, the prenatal anxiety was still associated with c-section with non-medical indication. The adjusted odd ratio for prenatal anxiety state, prenatal trait anxiety state and c-section with non-medical indication was 1.41 (95% CI: 1.06-1.87) and 1.23 (95% CI: 1.08-1.40), respectively. Conclusion: Prenatal anxiety state is a risk factor for c-section with non-medical indication.
    Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 10/2013; 38(10):1070-4.
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    ABSTRACT: Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
    Journal of Medicinal Chemistry 05/2013; · 5.61 Impact Factor
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    ABSTRACT: Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The co-crystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogs were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21 induction (2-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
    Journal of Medicinal Chemistry 04/2013; · 5.61 Impact Factor
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    ABSTRACT: Objective: To study the health status and explore the putative risk factors of chronic diseases among a Chinese rural population. Subjects and Methods: Face-to-face interviews were carried out to collect the information of social characteristics, health status and related risk factors of 11,909 families comprised of 49,383 subjects in the rural area of Liuyang, Hunan province during 2007. Chronic disease was diagnosed according to the diagnosis certification from the town clinic or superior level hospital. Results: The morbidity rate of chronic disease among Liuyang rural residents in 2007 was 19.22%. The prevalence of the top 10 chronic disorders was as follows: hypertension: 3.65%; urolithiasis: 1.03%; chronic obstructive pulmonary disease: 0.92%; ischemic heart disease: 0.92%; chronic gastritis: 0.91%; cerebrovascular disease: 0.71%; lumbar disk disease: 0.61%; chronic viral hepatitis: 0.55%; gallstones: 0.54%, and diabetes: 0.54%. Age, gender, educational level, occupation, marital status, type of housing, source of drinking water, smoking, underweight and overweight were factors associated with chronic disease. We also noticed that 14.2% of the residents were underweight and 29.7% are still using unsafe sources of drinking water. Conclusions: The prevalence of chronic disease in Liuyang area was severe both in communicable and noncommunicable chronic disease. Unhealthy lifestyles such as tobacco usage and overweight partially contributed to the high prevalence of chronic disease.
    Medical Principles and Practice 01/2013; · 0.96 Impact Factor
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    ABSTRACT: Potent and selective inhibitors of tankyrases have recently been characterized to bind to an induced pocket. Here we report the identification of a novel potent and selective tankyrase inhibitor that binds to both the nicotinamide pocket and the induced pocket. The crystal structure of human TNKS1 in complex with this "dual-binder" provides a molecular basis for their strong and specific interactions and suggests clues for the further development of tankyrase inhibitors.
    Journal of Medicinal Chemistry 01/2013; · 5.61 Impact Factor
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    ABSTRACT: Membrane proteins play critical roles in many biological processes and are the focus of intense biomedical research. One bottleneck for studying membrane proteins is the difficulty in expressing correctly folded and stable proteins, which often requires extensive protein engineering and multiple rounds of optimization, a time and resource intensive process. Here, we describe a method for rapidly screening membrane protein expression in insect cells. The method uses a green fluorescent protein (GFP) covalently fused to target membrane proteins and the resulting fusion proteins are then transiently expressed in insect cells. This approach enables us to dramatically reduce the time and resources required for expression screening by eliminating the need to create recombinant baculovirus. We show that transiently expressed membrane proteins can be directly monitored for their subcellular localizations by fluorescence microscopy. Moreover, their expression levels, approximate molecular mass, and stability can be evaluated with nanogram levels of unpurified proteins by ultrasensitive fluorescence-detection size exclusion chromatography (FSEC). We present our proof of principle studies using a homotrimeric ion channel (ASIC3) and a heterodimeric transporter (SLC7A5/SLC3A2) as examples, and demonstrate the utility of transient expression coupled with FSEC in optimizing membrane protein expression.
    Protein Expression and Purification 12/2012; · 1.43 Impact Factor
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    ABSTRACT: Casein kinase 1 epsilon (CK1e) and its closest homolog CK1d are key regulators of diverse cellular processes. We report two crystal structures of PF4800567, a potent and selective inhibitor of CK1e, bound to the kinase domains of human CK1d and CK1e as well as one apo CK1e crystal structure. These structures provide a molecular basis for the strong and specific inhibitor interactions with CK1e and suggest clues for further development of CK1e inhibitors.
    Journal of Medicinal Chemistry 10/2012; · 5.61 Impact Factor
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    ABSTRACT: Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel β-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.
    Journal of the American Chemical Society 09/2012; 134(41):17059-67. · 10.68 Impact Factor
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    ABSTRACT: Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.
    Bioorganic & medicinal chemistry letters 07/2012; 22(17):5392-5. · 2.65 Impact Factor
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    ABSTRACT: Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
    Journal of Medicinal Chemistry 04/2012; 55(11):4936-54. · 5.61 Impact Factor
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    Hakan Gunaydin, Yan Gu, Xin Huang
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    ABSTRACT: Tankyrases (TNKS1 and TNKS2) are key regulators of cellular processes such as telomere pathway and Wnt signaling. IWRs (inhibitors of Wnt response) have recently been identified as potent and selective inhibitors of tankyrases. However, it is not clear how these IWRs interact with tankyrases. Here we report the crystal structure of the catalytic domain of human TNKS1 in complex with IWR2, which reveals a novel binding site for tankyrase inhibitors. The TNKS1/IWR2 complex provides a molecular basis for their strong and specific interactions and suggests clues for further development of tankyrase inhibitors.
    PLoS ONE 01/2012; 7(3):e33740. · 3.73 Impact Factor
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    ABSTRACT: Casein kinase 1 delta (CK1δ) and its closest homologue CK1ε are key regulators of diverse cellular growth and survival processes such as Wnt signaling, DNA repair, and circadian rhythms. We report three crystal structures of the kinase domain of human CK1δ, one apo and two complexed with a potent and selective CK1δ/ε inhibitor PF670462 in two different crystal forms. These structures provide a molecular basis for the strong and specific inhibitor interactions and suggest clues for further development of CK1δ/ε inhibitors.
    Journal of Medicinal Chemistry 12/2011; 55(2):956-60. · 5.61 Impact Factor
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    ABSTRACT: Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.
    Journal of Medicinal Chemistry 11/2011; 54(24):8440-50. · 5.61 Impact Factor
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    ABSTRACT: To examine impact of cesarean delivery in first pregnancy on neonatal mortality and morbidity in second pregnancy. Retrospective cohort study using 1995-2002 US birth registration data. Neonatal mortality and morbidity in second pregnancy of cesarean deliveries in the first pregnancy were compared with vaginal deliveries in the first pregnancy. A total of 9,643,175 singleton second births were eligible in the analysis after excluding those with unknown delivery method (1,801,339 with a previous cesarean delivery and 7,841,836 with a previous vaginal delivery). Compared with vaginal delivery group, infants born to mothers with a previous cesarean delivery had increased risks of assisted ventilation (OR=1.47, 95% CI 1.46, 1.49), low Apgar's score (OR=1.14, 95% CI 1.12, 1.17), seizure (OR=1.36, 95% CI 1.27, 1.45), fetal distress (OR=1.46, 95% CI 1.44, 1.47), and asphyxia-related neonatal death (OR=1.40, 95% CI 1.29, 1.52). The association between mode of delivery in first pregnancy and neonatal outcomes in second pregnancy remained the same after excluding women with chronic health problems or adverse birth history and adjusting for potential confounding factors. Cesarean delivery in first pregnancy is associated with increased risks of neonatal morbidity and mortality in second pregnancy.
    European journal of obstetrics, gynecology, and reproductive biology 06/2011; 158(2):204-8. · 1.97 Impact Factor
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    ABSTRACT: To investigate the infection of hemorrhagic fever with renal syndrome (HFRS) in host animals and inapparent infection of HFRS in general population in Dongting Lake areas after floods. The night trapping method was used to capture rodents. The immunofluorescence assays were used to detect the hantavirus (HV) antigens and antibodies in rodents lung and in the serum of general population. Nonconditional logistic regression was applied to analyze risk factors for inapparent infection with HV. In flood region,draw-near flood region and new migration region,rodent density was 6.95%,6.28%, and 8.67%, respectively, and the virus-carrying rate in rodents was 15.07%,9.25%, and 4.47%, respectively. The virus-carrying rat index was the highest in flood region (0.10). Apodemus agrarius was the dominant species. The standardized positive rate of HV antibody in general population from above mentioned regions was 4.49%, 3.11%, and 3.13%, respectively. There was no significant difference among different age or gender groups. The results of logistic regression analysis indicated that people who were involved in construction of water conservancy facilities in winter or practice of rat extermination at home were the principal factors related to inapparent infection with HV. The virus-carrying rate in main host animals of HV in the 3 regions is high, whereas the positive rate of HV antibody is low in general population. Comprehensive measures should be taken to prevent and control HFRS, such as reinforcing surveillance of HFRS, strengthening deratization, and preventive inoculation.
    Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 03/2011; 36(3):223-8.
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    ABSTRACT: To explore the risk factors of hypertension in a rural area in Hunan Province. A population-based case-control study was used. In the first step, three villages in Liuyang were selected by stratified cluster random sampling method and all local residents were investigated by face-to-face interview. Then some patients with hypertension found in the first step were randomly sampled to case group, while healthy adults with no hypertension and in similar compositions of gender and age with the case group were selected to control group. Independent effects of risk factors were analyzed by Logistic regression, and the interaction among risk factors was analyzed by using an additive effects model. Effective investigation data for 218 patients in the case group and 182 healthy people in the control group were used. The main risk factors of hypertension in rural areas of Liuyang, Hunan province were overweight (OR = 4.048), obesity (OR = 6.476), central obesity (OR = 2.632), and family history of hypertension (OR = 2.527). After adjusting some confounding factors, significant positive interaction were observed between family history, overweight/obesity and central obesity; the relative excess risk of interaction (RERI), attributable proportion of interaction (API), and the interaction index (S) were 3.268 vs 0.569, 48.365% vs 14.880%, and 2.313 vs 1.249, respectively. The cause of hypertension in rural areas of Liuyang, Hunan province was closely related with overweight, obesity, central obesity and family hypertension history. There were positive interactions between family history and overweight/obesity and central obesity in the causes of hypertension.
    Wei sheng yan jiu = Journal of hygiene research 03/2011; 40(2):211-4.

Publication Stats

184 Citations
149.35 Total Impact Points

Institutions

  • 2013
    • The Second Xiangya Hospital of Central South University
      Ch’ang-sha-shih, Hunan, China
  • 2008–2013
    • Central South University
      • • School of Biological Science and Technology
      • • School of Public Health
      Changsha, Hunan, China
  • 2003–2011
    • Amgen
      • Department of Medicinal Chemistry
      Thousand Oaks, CA, United States