The identification of AF38469: An orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin

Schrøder, Tenna Juul; Christensen, Søren; Lindberg, Samsa; Langgård, Morten; David, Laurent; Maltas, Philip; Eskildsen, Jørgen; Jacobsen, Jørgen; Tagmose, Lena; Simonsen, Klaus B.; Rønn, Lars Christian B.; Jong, Inge E.M. de; Malik, Ibrahim; Karlsson, Jens-Jakob; Bundgaard, Christoffer; Egebjerg, Jan; Stavenhagen, Jeffrey B.; Strandbygård, Dorthe; Thirup, Søren; Andersen, Jacob Lauwring; Srinivas, U.; Pervaram, Sridhar; Kasturi, Shiva Prasad; Eradi, Pradheep; Sakumudi, Durga Rao; Watson, Stephen P.

doi:10.1016/j.bmcl.2013.11.046

Cited by 39 publications

(39 citation statements)

References 5 publications

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“…Recently, an orally bioavailable Sort1 inhibitor, AF38469, with an IC 50 value of 330 nM has been identified (38). To determine whether pharmacological inhibition of Sort1 with AF38469 might improve lipid homeostasis and inflammation, we fed mice WD supplemented with AF38469 to achieve an estimated 4 mg/kg daily dose, which was in line with the published pharmacokinetic data (38).…”

Section: Sort1 Inhibitor Reduced Plasma Cholesterol Levels Hepatic Vmentioning

confidence: 68%

“…This study provided proof-ofconcept evidence that pharmacological inhibition of Sort1 decreased plasma cholesterol in WD-fed mice. Previous characterization studies have shown that AF38469 is a potent, selective, and orally bioavailable Sort1 inhibitor (38). Given that hepatocyte Sort1 deletion lowered plasma cholesterol in WD-fed mice, it may be assumed that the hypocholesterolemic effect of AF38469 treatment may at least be partially mediated by hepatic Sort1 inhibition.…”

Section: Downloaded Frommentioning

confidence: 99%

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Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice

Chen

Matye

et al. 2019

Journal of Lipid Research

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Section: Sort1 Inhibitor Reduced Plasma Cholesterol Levels Hepatic Vmentioning

confidence: 68%

Section: Downloaded Frommentioning

confidence: 99%

Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice

Chen

Matye

et al. 2019

Journal of Lipid Research

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“…3A) [16]. Small molecules that bind to this site have been characterized [19]. The N-terminus of NT (pyroGlu-Leu-Tyr-Glu-Asn) also interacts with hsortilin [16].…”

Section: Resultsmentioning

confidence: 99%

Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells

Sparks

Guida

Sowden

et al. 2016

Biochemical and Biophysical Research Communications

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Studies examining the relationship between cellular sortilin and VLDL-B100 secretion demonstrate inconsistent results. Current studies explore the possibility that discrepancies may be related to insulin sensitivity. McArdle RH7777 cells (McA cells) cultured under serum enriched conditions lose sensitivity to insulin. Following incubation in serum-free DMEM containing 1% BSA, McA cells become insulin responsive and demonstrate reduced apo B secretion. Current studies indicate that insulin sensitive McA cells express lower cellular sortilin that corresponds with reduction in VLDL-B100 secretion without changes in mRNA of either sortilin or apo B. When sortilin expression is further reduced by siRNA knockdown (KD), there are additional decreases in VLDL-B100 secretion. A crystal structure of human sortilin (hsortilin) identifies two binding sites on the luminal domain for the N- and C-termini of neurotensin (NT). A small organic compound (cpd984) was identified that has strong theoretical binding to the N-terminal site. Both cpd984 and NT bind hsortilin by surface plasmon resonance. In incubations with insulin sensitive McA cells, cpd984 was shown to enhance VLDL-B100 secretion at each level of sortilin KD suggesting cpd984 acted through sortilin in mediating its effect. Current results support a role for sortilin to facilitate VLDL-B100 secretion which is limited to insulin sensitive McA cells. Inconsistent reports of the relationship between VLDL-B100 secretion and sortilin in previous studies may relate to differing functions of sortilin in VLDL-B100 secretion depending upon insulin sensitivity.

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“…NT was found to bind within the tunnel of the b-propeller domain via its three C-terminal residues, YIL, 11 and we have recently shown that also small molecule inhibitors of NT binding occupies this YIL binding site. 12,13 Here we have set out to further study the structural properties of sortilin and the binding of NT using a broad biophysical approach. The data provided here suggest that NT is completely contained inside the tunnel of the b-propeller, firmly bound by its C-terminus in the previously reported binding site, and further attached by its N-terminal part at a low affinity site on the opposite side of the tunnel.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin

et al. 2014

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Sortilin is a multifunctional receptor involved in sorting and apoptosis. We have previously reported a 2.0-Å structure of the Vps10 ectodomain in complex with one of its ligands, the tridecapeptide neurotensin. Here we set out to further characterize the structural properties of sortilin and its interaction with neurotensin. To this end, we have determined a new 2.7 Å structure using a crystal grown with a 10-fold increased concentration of neurotensin. Here a second peptide fragment was observed within the Vps10 b-propeller, which may in principle either represent a second molecule of neurotensin or the N-terminal part of the molecule bound at the previously identified binding site. However, in vitro binding experiments strongly favor the latter hypothesis. Neurotensin thus appears to bind with a 1:1 stoichiometry, and whereas the N-terminus does not bind on its own, it enhances the affinity in context of full-length neurotensin. We conclude that the N-terminus of neurotensin probably functions as an affinity enhancer for binding to sortilin by engaging the second binding site. Crystal packing differs partly from the previous structure, which may be due to variations in the degree and pattern of glycosylations. Consequently, a notable hydrophobic loop, not modeled previously, could now be traced. A computational analysis suggests that this and a neighboring loop may insert into the membrane and thus restrain movement of the Vps10 domain. We have, furthermore, mapped all N-linked glycosylations of CHO-expressed human sortilin by mass spectrometry and find that their locations are compatible with membrane insertion of the hydrophobic loops.

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The identification of AF38469: An orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin

Cited by 39 publications

References 5 publications

Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice

Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice

Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells

Revisiting the structure of the Vps10 domain of human sortilin and its interaction with neurotensin

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