MedKoo product information:

  TG101348

TG101348 is a  JAK2 inhibitor, is also an orally bioavailable, small-molecule, ATP-competitive inhibitor of Janus-associated kinase 2 (JAK2) with potential antineoplastic activity. JAK2 inhibitor TG101348 competes with JAK2 as well as the mutated form AK2V617F for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and the induction of tumor cell apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders (MPDs); the mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer: TargeGen (acquired by Sanofi-Aventis)

General activitiy: TG101348 (SAR302503) was developed for the treatment of patients with myeloproliferative diseases including myelofibrosis. TG101348 acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM).  In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to supression of proliferation and induction of apoptosis. Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348. Phase I trial results focused on safety and efficacy of TG101348 in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011. Compound was originally discovered TargeGen then acquired by Sanofi-Aventis who continues its development under the code SAR302503. (source: http://en.wikipedia.org/wiki/TG101348 )

Safety and efficacy of TG101348 in myelofibrosis: Scientitsts from Mayo Clinic recently reported that TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. (source: J Clin Oncol. 2011 Mar 1;29(7):789-96)

Efficacy of TG101348. Scientists from Harvard Medical School recently reported that TG101348  had an in vitro IC50 of approximately 3 nM, showed therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5. (source: Cancer Cell. 2008 Apr;13(4):311-20.)

1: Stein BL, Crispino JD, Moliterno AR. Janus kinase inhibitors: an update on the progress and promise of targeted therapy in the myeloproliferative neoplasms. Curr Opin Oncol. 2011 Nov;23(6):609-16. Review. PubMed PMID: 21993415.

2: Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, Sattler M. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2011 Sep 16. doi: 10.1038/leu.2011.255. [Epub ahead of print] PubMed PMID: 21926964.

3: Betts BC, Abdel-Wahab O, Curran SA, St Angelo ET, Koppikar P, Heller G, Levine RL, Young JW. Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen. Blood. 2011 Nov 10;118(19):5330-9. Epub 2011 Sep 13. PubMed PMID: 21917753; PubMed Central PMCID: PMC3217413.

4: Looi CY, Imanishi M, Takaki S, Sato M, Chiba N, Sasahara Y, Futaki S, Tsuchiya S, Kumaki S. Octa-arginine mediated delivery of wild-type Lnk protein inhibits TPO-induced M-MOK megakaryoblastic leukemic cell growth by promoting apoptosis. PLoS One. 2011;6(8):e23640. Epub 2011 Aug 10. PubMed PMID: 21853157; PubMed Central PMCID: PMC3154509.

5: Passamonti F, Maffioli M, Caramazza D, Cazzola M. Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget. 2011 Jun;2(6):485-90. PubMed PMID: 21646683.

6: Pardanani A, Tefferi A. Targeting myeloproliferative neoplasms with JAK inhibitors. Curr Opin Hematol. 2011 Mar;18(2):105-10. Review. PubMed PMID: 21245760.

7: Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011 Mar 1;29(7):789-96. Epub 2011 Jan 10. PubMed PMID: 21220608.

8: Pardanani A, Vannucchi AM, Passamonti F, Cervantes F, Barbui T, Tefferi A. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia. 2011 Feb;25(2):218-25. Epub 2010 Nov 16. Review. PubMed PMID: 21079613.

9: Mullally A, Lane SW, Ball B, Megerdichian C, Okabe R, Al-Shahrour F, Paktinat M, Haydu JE, Housman E, Lord AM, Wernig G, Kharas MG, Mercher T, Kutok JL, Gilliland DG, Ebert BL. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010 Jun 15;17(6):584-96. PubMed PMID: 20541703; PubMed Central PMCID: PMC2909585.

10: Cotto M, Cabanillas F, Tirado M, García MV, Pacheco E. Epigenetic therapy of lymphoma using histone deacetylase inhibitors. Clin Transl Oncol. 2010 Jun;12(6):401-9. Review. PubMed PMID: 20534395.

11: Lasho T, Tefferi A, Pardanani A. Inhibition of JAK-STAT signaling by TG101348: a novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells. Leukemia. 2010 Jul;24(7):1378-80. Epub 2010 May 20. PubMed PMID: 20485374.

12: Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-42. Review. PubMed PMID: 20008249.

13: Mesa RA, Tefferi A. Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. Expert Opin Emerg Drugs. 2009 Sep;14(3):471-9. Review. PubMed PMID: 19552608.

14: Geron I, Abrahamsson AE, Barroga CF, Kavalerchik E, Gotlib J, Hood JD, Durocher J, Mak CC, Noronha G, Soll RM, Tefferi A, Kaushansky K, Jamieson CH. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell. 2008 Apr;13(4):321-30. PubMed PMID: 18394555.

15: Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, Gozo M, McDowell EP, Levine RL, Doukas J, Mak CC, Noronha G, Martin M, Ko YD, Lee BH, Soll RM, Tefferi A, Hood JD, Gilliland DG. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008 Apr;13(4):311-20. PubMed PMID: 18394554.

16: Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia. 2008 Sep;22(9):1790-2. Epub 2008 Mar 20. PubMed PMID: 18354492.