Discovery of -(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives As Potent and Selective JAK2 Inhibitors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Aug 16

PMID 37583815

Authors

Yang Tian

Songhui Qin

Fang Zhang

Jing Luo

Xi He

Yi Sun

Tao Yang

Affiliations

Soon will be listed here.

Abstract

The JAK2 mutation leads to JAK2 autophosphorylation and activation of downstream pathways, eventually resulting in myeloproliferative neoplasms (MPNs). Selective inhibitors showed advantages in terms of side effects; therefore, there is an urgent need to develop novel selective JAK2 inhibitors for treating MPNs. In this study, we described a series of -(4-(aminomethyl)phenyl)pyrimidin-2-amine derivatives as selective JAK2 inhibitors. Systematic exploration through opening the tetrahydroisoquinoline based on the previous lead compound led to the discovery of the optimal compound . Compound showed excellent potency on JAK2 kinase, with an IC value of 5 nM, and inhibited the phosphorylation of JAK2 and its downstream signaling pathway. Moreover, exhibited 38.6-, 54.6-, and 41.2-fold selectivity for JAK1, JAK3, and TYK2, respectively. Compared to the lead compound, demonstrated much better metabolic stabilities, with a bioavailability of 41.1%. These findings suggest that is a relatively selective JAK2 inhibitor, deserving to be developed for treating MPNs.

References

Barbui T, Thiele J, Gisslinger H, Kvasnicka H, Vannucchi A, Guglielmelli P . The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018; 8(2):15. PMC: 5807384. DOI: 10.1038/s41408-018-0054-y. View

Harrison C, Vannucchi A, Platzbecker U, Cervantes F, Gupta V, Lavie D . Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017; 5(2):e73-e81. DOI: 10.1016/S2352-3026(17)30237-5. View

Honda A, Kuramoto K, Niwa T, Naito H . NS-018 reduces myeloma cell proliferation and suppresses osteolysis through inhibition of the JAK2 and Src signaling pathways. Blood Cancer J. 2018; 8(7):62. PMC: 6018113. DOI: 10.1038/s41408-018-0098-z. View

Bose P, Verstovsek S . JAK2 inhibitors for myeloproliferative neoplasms: what is next?. Blood. 2017; 130(2):115-125. PMC: 5510786. DOI: 10.1182/blood-2017-04-742288. View

Shuai K, Liu B . Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003; 3(11):900-11. DOI: 10.1038/nri1226. View

Mullally A, Hood J, Harrison C, Mesa R . Fedratinib in myelofibrosis. Blood Adv. 2020; 4(8):1792-1800. PMC: 7189288. DOI: 10.1182/bloodadvances.2019000954. View

Mesa R, Vannucchi A, Mead A, Egyed M, Szoke A, Suvorov A . Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017; 4(5):e225-e236. PMC: 8209752. DOI: 10.1016/S2352-3026(17)30027-3. View

William A, Lee A, Goh K, Blanchard S, Poulsen A, Teo E . Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs),.... J Med Chem. 2011; 55(1):169-96. DOI: 10.1021/jm201112g. View

Plosker G . Ruxolitinib: a review of its use in patients with myelofibrosis. Drugs. 2015; 75(3):297-308. DOI: 10.1007/s40265-015-0351-8. View

10.

Ihle J, Kerr I . Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995; 11(2):69-74. DOI: 10.1016/s0168-9525(00)89000-9. View

11.

Verstovsek S, Kantarjian H, Estrov Z, Cortes J, Thomas D, Kadia T . Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012; 120(6):1202-9. PMC: 4081158. DOI: 10.1182/blood-2012-02-414631. View

12.

Santos F, Kantarjian H, Jain N, Manshouri T, Thomas D, Garcia-Manero G . Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2009; 115(6):1131-6. PMC: 4081385. DOI: 10.1182/blood-2009-10-246363. View

13.

Pikman Y, Lee B, Mercher T, McDowell E, Ebert B, Gozo M . MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3(7):e270. PMC: 1502153. DOI: 10.1371/journal.pmed.0030270. View

14.

Hexner E, Serdikoff C, Jan M, Swider C, Robinson C, Yang S . Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2007; 111(12):5663-71. PMC: 2424161. DOI: 10.1182/blood-2007-04-083402. View

15.

Gangat N, Begna K, Al-Kali A, Hogan W, Litzow M, Pardanani A . Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor. Blood Cancer J. 2023; 13(1):3. PMC: 9813003. DOI: 10.1038/s41408-022-00780-9. View

16.

Goh K, Novotny-Diermayr V, Hart S, Ong L, Loh Y, Cheong A . TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia. 2011; 26(2):236-43. DOI: 10.1038/leu.2011.218. View

17.

Yu H, Pardoll D, Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009; 9(11):798-809. PMC: 4856025. DOI: 10.1038/nrc2734. View

18.

Levine R, Wadleigh M, Cools J, Ebert B, Wernig G, Huntly B . Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005; 7(4):387-97. DOI: 10.1016/j.ccr.2005.03.023. View

19.

Levine R, Pardanani A, Tefferi A, Gilliland D . Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007; 7(9):673-83. DOI: 10.1038/nrc2210. View

20.

Ioannidis S, Lamb M, Wang T, Almeida L, Block M, Davies A . Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway. J Med Chem. 2010; 54(1):262-76. DOI: 10.1021/jm1011319. View