The Recent Medicinal Chemistry Development of Jak2 Tyrosine Kinase Small Molecule Inhibitors

Luo

et al. 2013

Background/Aims: Janus-activated kinase-2 JAK2 participates in the signaling of several hormones including growth hormone, fosters tumor growth and modifies the activity of several Na⁺ coupled nutrient transporters. Peptide uptake into intestinal and tumor cells is accomplished by electrogenic peptide transporters PEPT1 and PEPT2. The present study thus explored whether JAK2 contributes to the regulation of PEPT1 and PEPT2 activity. Methods: cRNA encoding either PEPT1 or PEPT2 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, constitutively active ^V617FJAK2 or inactive ^K882EJAK2. The current created by the dipeptide glycine-glycine (I_gly-gly) was determined by dual electrode voltage clamp and taken as measure for electrogenic peptide transport. Results: No appreciable I_gly-gly was observed in water injected oocytes. In PEPT1 or PEPT2 expressing oocytes I_gly-gly was significantly increased by additional coexpression of JAK2. As shown in PEPT1 expressing oocytes, I_gly-gly without significantly modifying the concentration required for halfmaximal I_gly-gly (K_M). Following disruption of carrier insertion with brefeldin A (5 µM) I_gly-gly declined similarly fast in Xenopus oocytes expressing PEPT1 with JAK2 and in Xenopus oocytes expressing PEPT1 alone. In oocytes expressing both, PEPT1 and ^V617FJAK2, I_gly-gly was gradually decreased by JAK2 inhibitor AG490 (40 µM). According to Ussing chamber experiments pharmacological JAK2 inhibition similarly decreased I_gly-gly in mouse intestine. Conclusion: Regulation of the peptide transporters PEPT and PEPT2 does involve the Janus-activated kinase-2 JAK2.

Section: Introductionmentioning

confidence: 99%

Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2

Luo

et al. 2013

“…JAK2 contributes to the signaling of neoplasms and JAK2 inhibitors are considered as drugs in the treatment of myeloproliferative disorders [5][6][7][8][9][10][11]. The gain of function mutation V617F JAK2 is observed in the majority of myeloproliferative diseases [12].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of ClC-2 by JAK2

Läng

2012

JAK2 (Janus kinase-2) is activated by cell shrinkage and may thus participate in cell volume regulation. Cell volume regulatory ion channels include the small conductance Cl^-channels ClC-2. The present study thus explored whether JAK2 influences ClC-2 activity. To this end, ClC-2 was expressed in Xenopus oocytes with or without wild type JAK2, active ^V617FJAK2 or inactive ^K882EJAK2 and the Cl channel activity determined by dual electrode voltage clamp. Expression of ClC-2 was followed by a marked increase of cell membrane conductance. The conductance was significantly decreased following coexpression of JAK2 or ^V617FJAK2, but not by coexpression of ^K882EJAK2. Exposure of the oocytes expressing ClC-2 together with ^V617FJAK2 to the JAK2 inhibitor AG490 (40 µM) resulted in a gradual increase of the conductance. According to chemiluminescence JAK2 decreased the channel protein abundance in the cell membrane. The decline of conductance in ClC-2 and ^V617FJAK2 coexpressing oocytes following inhibition of channel protein insertion by brefeldin A (5 µM) was similar in oocytes expressing ClC-2 with ^V617FJAK2 and oocytes expressing ClC-2 alone, indicating that ^V617FJAK2 might slow channel protein insertion into rather than accelerating channel protein retrieval from the cell membrane. In conclusion, JAK2 down-regulates ClC-2 activity and thus counteracts Cl^-exit, an effect which may impact on cell volume regulation.

“…Excessive JAK2 activity fosters the development of malignancy and JAK2 inhibitors may be effective in the treatment of myeloproliferative disorders [7][8][9][10][11][12]. The gain of function mutation V617F JAK2 presumably contributes to the pathogenesis of myeloproliferative disease [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of the Myoinositol Transporter SMIT by JAK2

Läng

2012

Background/Aims: Janus-activated kinase-2 JAK2 is activated by energy depletion and hyperosmotic shock and modifies the activity of several Na⁺ coupled transporters. The Na⁺ coupled osmolyte transporter SMIT (myoinositol transporter) is upregulated by osmotic shock and downregulated by energy depletion. The present study thus explored whether JAK2 contributes to the regulation of SMIT activity. Methods: To this end, cRNA encoding SMIT was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, constitutively active ^V617FJAK2 or inactive ^K882EJAK2. Inositol-induced current (I_SMIT) was determined by dual electrode voltage clamp and taken as measure for electrogenic inositol transport. Results: No appreciable I_SMIT was observed in water injected oocytes. In SMIT expressing oocytes I_SMIT was significantly decreased by additional coexpression of JAK2 or ^V617FJAK2, but not by coexpression of ^K882EJAK2. According to kinetic analysis coexpression of JAK2 decreased maximal I_SMIT without significantly modifying the concentration required for halfmaximal I_SMIT (K_M). In oocytes expressing both, SMIT and JAK2, ISMIT was gradually increased by JAK2 inhibitor AG490 (40 µM). Disruption of carrier insertion with brefeldin A (5 µM) was followed by a decline of I_SMIT to a similar extent in Xenopus oocytes expressing SMIT with JAK2 and in Xenopus oocytes expressing SMIT alone, suggesting that JAK2 did not affect carrier stability in the cell membrane. Conclusion: JAK2 contributes to the regulation of the inositol transporter SMIT.