|To: scaram(o)uche who wrote (381)||1/17/2019 9:02:09 AM|
|Well....... PRs of course often don't tell entire story, but second generation molecule is incredibly effective, second cohort of a phase II study. PR suggests no safety signal....|
Don't know if company has described difference between beloranib and 1061, described off target tox for beloranib. If it has, this is worth watching.
|RecommendKeepReplyMark as Last ReadRead Replies (2)|
|To: scaram(o)uche who wrote (423)||1/17/2019 9:24:48 AM|
|J Pharmacol Exp Ther. 2018 May;365(2):301-313. doi: 10.1124/jpet.117.246272. Epub 2018 Feb 28.|
Preclinical Efficacy and Safety of the Novel Antidiabetic, Antiobesity MetAP2 Inhibitor ZGN-1061.
Burkey BF1, Hoglen NC2, Inskeep P2, Wyman M2, Hughes TE2, Vath JE2.
Zafgen, Inc., Boston, Massachusetts (B.F.B., N.C.H., M.W., T.E.H., J.E.V.) and InskeepDMPK, LLC (P.I.), East Lyme, Connecticut firstname.lastname@example.org.
Zafgen, Inc., Boston, Massachusetts (B.F.B., N.C.H., M.W., T.E.H., J.E.V.) and InskeepDMPK, LLC (P.I.), East Lyme, Connecticut.
Methionine aminopeptidase 2 (MetAP2) inhibition is a promising approach to treating diabetes, obesity, and associated metabolic disorders. Beloranib, a MetAP2 inhibitor previously investigated for treatment of Prader-Willi syndrome, was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs). Here, we report the pharmacological characterization of ZGN-1061, a novel MetAP2 inhibitor being investigated for treatment of diabetes and obesity. Four weeks of subcutaneous administration of ZGN-1061 to diet-induced obese (DIO) insulin-resistant mice produced a 25% reduction in body weight, primarily due to reduced fat mass, that was comparable to beloranib. ZGN-1061 also produced improvements in metabolic parameters, including plasma glucose and insulin, and, in HepG2 cells, initiated gene changes similar to beloranib that support observed in vivo pharmacodynamics. In vitro studies in ECs demonstrated that ZGN-1061 effects on EC proliferation and coagulation proteins were greatly attenuated, or absent, relative to beloranib, due to lower intracellular drug concentrations, shorter half-life of inhibitor-bound MetAP2 complex, and reduced cellular enzyme inhibition. In dogs, ZGN-1061 was more rapidly absorbed and cleared, with a shorter half-life than beloranib. Unlike beloranib, ZGN-1061 did not increase coagulation markers in dogs, and ZGN-1061 had a greatly improved safety profile in rats relative to beloranib. In conclusion, ZGN-1061 and beloranib demonstrated similar efficacy in a mouse model of obesity, while ZGN-1061 had a markedly improved safety profile in multiple in vitro and in vivo models. The lower duration of exposure characteristic of ZGN-1061 is expected to provide a meaningfully enhanced clinical safety profile.
|RecommendKeepReplyMark as Last Read|
|To: scaram(o)uche who wrote (423)||1/17/2019 1:13:04 PM|
|From: Miljenko Zuanic|
<The FDA cited the possibility of cardiovascular (CV) safety risk based on the Company’s prior compound and outlined multiple potential paths for moving forward, including nonclinical or clinical options, to address these concerns in the ongoing development of ZGN-1061. The Company plans to assess these options and request a Type A meeting with the Agency to discuss next steps with the program.>
Beloranib-preclinical: <CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] is a new fumagillin anticancer drug that belongs to an angiogenesis inhibitor. Its effect on the central nervous system (CNS), general behavior, cardiovascular-respiratory system and the other organ systems were studied. CKD-732 was intravenously administered with the dosages of 10, 30, 40 or 50 mg/kg and the highest dosage of 50 mg/kg prolonged the hexobarbital-induced sleep time.>
|RecommendKeepReplyMark as Last ReadRead Replies (1)|
|To: Miljenko Zuanic who wrote (425)||1/17/2019 2:33:06 PM|
|Thanks. Here is the phase I.....|
>> ZGN-1061 is not readily distributed to the central nervous system and, therefore, may not be expected to result in comparable sleep-related AEs. <<
>> Four subjects (3 in the 0.6?mg ZGN-1061 group and 1 in the 1.8?mg ZGN-1061 group in the MAD phase) had D-dimer levels that exceeded the upper limit of normal (ULN) by >1.5-fold (0.81?mg/L FEU). None of these elevations was found to be indicative of VTE. These elevations occurred as a single isolated measurement, that is, occurred during the follow-up period, 28?days post-last dose (n?=?1), or coincided with known non-VTE related causes of D-dimer elevation (sampling from blocked catheter [n?=?1], tooth infection/root canal [n?=?1], multiple hematomas at venipuncture sites [n?=?1]). <<
Molecule clearly differentiates from belanorib, but it's a four week trial.
|RecommendKeepReplyMark as Last Read|
|From: scaram(o)uche||1/18/2019 4:41:56 PM|
|Diabetes Metab Syndr Obes. 2018 Sep 28;11:565-577. doi: 10.2147/DMSO.S171109. eCollection 2018.|
Comprehensive comparison of MetAP2 tissue and cellular expression pattern in lean and obese rodents.
Han J1, Tang Y1, Lu M1, Hua H1.
Lilly China Research and Development Center, Shanghai, People's Republic of China,
Methionine aminopeptidase 2 (MetAP2) cleaves the initiator methionine from nascent peptides during translation. In both preclinical and clinical studies, the pharmacological inhibition of MetAP2 in obese subjects results in the suppression of food intake and body weight loss. However, the mechanism of action of body weight loss caused by MetAP2 inhibition remains to be elucidated, and the sites of action by pharmacological MetAP2 inhibition remain unknown.
In the present study, a comprehensive analysis of the MetAP2 expression pattern in mice was performed.
Except for the relatively low expression in adipose tissues, MetAP2 protein was well-expressed in tissues important for metabolism, including liver, whole brain, skeletal muscle and intestine tissues. In comparison to lean mice, MetAP2 mRNA level was elevated in the intestines of diet-induced obese (DIO) mice. At the cellular level, MetAP2 exhibited a distinct high expression in central and peripheral neurons, as well as in epithelial cells lining both the small intestine and colon. In the liver of lean mice, MetAP2 protein exhibited punctate staining, which was enriched in zone three hepatocytes surrounding the central veins. In contrast, MetAP2 expression was diffuse in the liver of DIO mice. Furthermore, MetAP2 was highly expressed in immune cells that infiltrated DIO livers.
Overall, these results delineate the MetAP2 expression at both tissue and cellular levels and highlight the altered MetAP2 expression under pathological conditions.
|RecommendKeepReplyMark as Last ReadRead Replies (1)|
|From: scaram(o)uche||7/24/2019 6:27:03 PM|
|rings a bell, may have already put this up and now it's back as eCollection.....|
PLoS One. 2019 Jul 23;14(7):e0220025. doi: 10.1371/journal.pone.0220025. eCollection 2019.
Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study.
Chung H1, Fierro A2, Pessoa-Mahana CD1.
Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile.
Organic Chemistry Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile.
Recent evidence has raised in discussion the possibility that cannabidiol can act as a negative allosteric modulator of the cannabinoid type 1 receptor. Here we have used computational methods to study the modulation exerted by cannabidiol on the effects of delta-9-tetrahydrocannabinol in the cannabinoid receptor type 1 and the possibility of direct receptor blockade. We propose a putative allosteric binding site that is located in the N-terminal region of receptor, partially overlapping the orthosteric binding site. Molecular dynamics simulations reveled a coordinated movement involving the outward rotation of helixes 1 and 2 and subsequent expansion of the orthosteric binding site upon cannabidiol binding. Finally, changes in the cytoplasmic region and high helix 8 mobility were related to impaired receptor internalization. Together, these results offer a possible explanation to how cannabidiol can directly modulate effects of delta-9-tetrahydrocannabinol on the cannabinoid receptor type 1.
|RecommendKeepReplyMark as Last Read|
|From: scaram(o)uche||10/30/2019 3:26:54 PM|
|Neuroscience. 2019 Sep 11. pii: S0306-4522(19)30650-5. doi: 10.1016/j.neuroscience.2019.09.005. [Epub ahead of print]|
Combined Loss of Ghrelin Receptor and Cannabinoid CB1 Receptor in Mice Decreases Survival but Does Not Additively Reduce Body Weight or Eating.
Mani BK1, Castorena CM1, Vianna CR1, Lee CE1, Metzger NP1, Vijayaraghavan P1, Osborne-Lawrence S1, Elmquist JK2, Zigman JM3.
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States of America. Electronic address: email@example.com.
Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (GHSR) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. Here, we hypothesized that the cannabinoid CB1 receptor (CB1R) may encode this putative redundancy, and as such, that genetic deletion of both GHSR and CB1R would exaggerate the metabolic deficits associated with deletion of GHSR alone. To test this hypothesis, we assessed food intake, BW, blood glucose, survival, and plasma acyl-ghrelin in ad libitum-fed male wild-type mice and those that genetically lack GHSR (GHSR-nulls), CB1R (CB1R-nulls), or both GHSR and CB1R (double-nulls). BW, fat mass, and lean mass were similar in GHSR-nulls and wild-types, lower in CB1R-nulls, but not further reduced in double-nulls. Food intake, plasma acyl-ghrelin, and blood glucose were similar among genotypes. Deletion of either GHSR or CB1R alone did not have a statistically-significant effect on survival, but double-nulls demonstrated a statistical trend towards decreased survival (p?=?0.07). We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.
Front Behav Neurosci. 2019 Aug 14;13:184. doi: 10.3389/fnbeh.2019.00184. eCollection 2019.
Endocannabinoids Interact With the Dopaminergic System to Increase Sexual Motivation: Lessons From the Sexual Satiety Phenomenon.
Canseco-Alba A1, Rodríguez-Manzo G1.
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav-Sede Sur), Ciudad de México, México.
In male rats, copulation to satiety induces a long-lasting sexual inhibitory state, considered to rely on a decreased sexual motivation. Dopaminergic transmission at the mesolimbic system plays a central role in the regulation of male sexual motivation. Endocannabinoids (eCBs) modulate the activity of the mesolimbic system and both dopamine (DA) and cannabinoid receptor activation reverses the sexual inhibition that characterizes sexually satiated rats. The eCB anandamide reverses sexual satiety when systemically administered or infused into the ventral tegmental area (VTA), the region where the activity of mesolimbic dopaminergic neurons is regulated. Thus, it could be thought that sexual motivation is diminished during the long-lasting sexual inhibition of sexually satiated rats and that eCBs reverse that inhibition through the modulation of the dopaminergic system. To test this hypothesis, we assessed the motivational state of sexually satiated male rats and determined if 2-arachidonoylglycerol (2-AG), the most abundant eCB and a full cannabinoid receptor agonist, also reversed the sexual inhibitory state. To establish the possible interaction between 2-AG and anandamide with the dopaminergic system for the reversal of sexual satiety, we analyzed the effects of the co-administration of each eCB and DA receptor agonists or antagonists. Results showed that 24-h after copulation to satiety, when the sexual inhibition is well established, the males' sexual motivation is diminished as measured in the sexual incentive motivation test. 2-AG, similarly to anandamide, reverses sexual satiety through the activation of CB1 receptors and both eCBs interact with the dopaminergic system to reverse the sexual inhibitory state. 2-AG effects are mediated by the modulation of the D2-like DA receptor family, whereas anandamide's effects are clearly mediated by the modulation of the D1-like DA receptor family and the activation of D2-like DA receptors. Present results evidence that a reduced sexual motivation underlies the sexual inhibitory state of sexually satiated rats and support the notion that eCBs reverse sexual satiety by modulating dopaminergic transmission, presumably at the mesolimbic system. Anandamide and 2-AG have a different interaction with D1-like and D2-like DA receptor families. Altogether present data endorse the association of the eCB system with the regulation of the motivational tone at the mesolimbic system.
Nat Chem Biol. 2019 Oct 28. doi: 10.1038/s41589-019-0387-2. [Epub ahead of print]
Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.
Shao Z1, Yan W1, Chapman K2, Ramesh K2, Ferrell AJ2, Yin J2, Wang X1, Xu Q3, Rosenbaum DM4.
Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
GM/CA, Advanced Photon Source, Argonne National Laboratory, Argonne, IL, USA.
Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA. firstname.lastname@example.org.
The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.
|RecommendKeepReplyMark as Last Read|
|From: scaram(o)uche||10/31/2019 11:48:11 AM|
|Front Mol Neurosci. 2019 Sep 20;12:224. doi: 10.3389/fnmol.2019.00224. eCollection 2019.|
Systematic Affinity Purification Coupled to Mass Spectrometry Identified p62 as Part of the Cannabinoid Receptor CB2 Interactome.
Sharaf A1, Mensching L1, Keller C1, Rading S1, Scheffold M1,2, Palkowitsch L3, Djogo N1, Rezgaoui M4, Kestler HA5, Moepps B2, Failla AV6, Karsak M1.
Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Pharmacology and Toxicology, Ulm University, Ulm, Germany.
Institute of Physiological Chemistry, Ulm University, Ulm, Germany.
Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
Institute of Medical Systems Biology, Ulm University, Ulm, Germany.
Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
The endocannabinoid system (ECS) consists particularly of cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands, and enzymes that synthesize and degrade their ligands. It acts in a variety of organs and disease states ranging from cancer progression over neuropathic pain to neurodegeneration. Protein components engaged in the signaling, trafficking, and homeostasis machinery of the G-protein coupled CB2, are however largely unknown. It is therefore important to identify further interaction partners to better understand CB2 receptor functions in physiology and pathophysiology. For this purpose, we used an affinity purification and mass spectrometry-based proteomics approach of Strep-HA-CB2 receptor in HEK293 cells. After subtraction of background interactions and protein frequency library assessment we could identify 83 proteins that were classified by the identification of minimally 2 unique peptides as highly probable interactors. A functional protein association network analysis obtained an interaction network with a significant enrichment of proteins functionally involved in protein metabolic process, in endoplasmic reticulum, response to stress but also in lipid metabolism and membrane organization. The network especially contains proteins involved in biosynthesis and trafficking like calnexin, Sec61A, tubulin chains TUBA1C and TUBB2B, TMED2, and TMED10. Six proteins that were only expressed in stable CB2 expressing cells were DHC24, DHRS7, GGT7, HECD3, KIAA2013, and PLS1. To exemplify the validity of our approach, we chose a candidate having a relatively low number of edges in the network to increase the likelihood of a direct protein interaction with CB2 and focused on the scaffold/phagosomal protein p62/SQSTM1. Indeed, we independently confirmed the interaction by co-immunoprecipitation and immunocytochemical colocalization studies. 3D reconstruction of confocal images furthermore showed CB2 localization in close proximity to p62 positive vesicles at the cell membrane. In summary, we provide a comprehensive repository of the CB2 interactome in HEK293 cells identified by a systematic unbiased approach, which can be used in future experiments to decipher the signaling and trafficking complex of this cannabinoid receptor. Future studies will have to analyze the exact mechanism of the p62-CB2 interaction as well as its putative role in disease pathophysiology.
Molecules. 2019 Oct 12;24(20). pii: E3672. doi: 10.3390/molecules24203672.
Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure.
Booth WT1, Walker NB2, Lowther WT3,4, Howlett AC5,6.
Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. email@example.com.
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. firstname.lastname@example.org.
Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. email@example.com.
Center for Molecular Signaling, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC 27109, USA. firstname.lastname@example.org.
Center for Molecular Signaling, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC 27109, USA. email@example.com.
Department of Physiology and Pharmacology, Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. firstname.lastname@example.org.
Cannabinoid receptor interacting protein 1a (CRIP1a) is an important CB1 cannabinoid receptor-associated protein, first identified from a yeast two-hybrid screen to modulate CB1-mediated N-type Ca2+ currents. In this paper we review studies of CRIP1a function and structure based upon in vitro experiments and computational chemistry, which elucidate the specific mechanisms for the interaction of CRIP1a with CB1 receptors. N18TG2 neuronal cells overexpressing or silencing CRIP1a highlighted the ability of CRIP1 to regulate cyclic adenosine 3',5'monophosphate (cAMP) production and extracellular signal-regulated kinase (ERK1/2) phosphorylation. These studies indicated that CRIP1a attenuates the G protein signaling cascade through modulating which Gi/o subtypes interact with the CB1 receptor. CRIP1a also attenuates CB1 receptor internalization via ß-arrestin, suggesting that CRIP1a competes for ß-arrestin binding to the CB1 receptor. Predictions of CRIP1a secondary structure suggest that residues 34-110 are minimally necessary for association with key amino acids within the distal C-terminus of the CB1 receptor, as well as the mGlu8a metabotropic glutamate receptor. These interactions are disrupted through phosphorylation of serines and threonines in these regions. Through investigations of the function and structure of CRIP1a, new pharmacotherapies based upon the CRIP-CB1 receptor interaction can be designed to treat diseases such as epilepsy, motor dysfunctions and schizophrenia.
|RecommendKeepReplyMark as Last Read|
|From: scaram(o)uche||11/15/2019 11:48:13 AM|
|Full circle in this thread, MetAP-2 inhibitors back to cancer (think zfgn)......|
J Med Chem. 2019 Nov 14. doi: 10.1021/acs.jmedchem.9b01070. [Epub ahead of print]
Identification of Methionine Aminopeptidase-2 (MetAP-2) inhibitor M8891, a Clinical Compound for the Treatment of Cancer.
Heinrich T, Seenisamy J, Becker F, Blume B, Bomke J, Dietz M, Eckert U, Friese-Hamim M, Gunera J, Hansen K, Leuthner B, Musil D, Pfalzgraf J, Rohdich F, Siegl C, Spuck D, Wegener A, Zenke FT.
The recently disclosed next generation of reversible, selective and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound 1a suffered from enterohepatic circulation preventing further development. Nevertheless, 1a was used as starting point for further optimization. Maintaining potent anti-proliferation activity while improving other compound properties enabled the generation of an attractive array of new MetAP-2 inhibitors. Identification of the most promising derivatives was driven by a multiparameter analysis of the compound properties. High affinity, long residence time, high permeability and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line was key for selection of candidates for in vivo efficacy evaluations. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to nomination of the clinical development compound M8891 which is currently in Phase I clinical testing in oncology patients.
and here's the phase I trial.......
|RecommendKeepReplyMark as Last Read|