UNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jul 29

PMID 25068800

Citations 85

Authors

Weihe Zhang

Deborah DeRyckere

Debra Hunter

Jing Liu

Michael A Stashko

Katherine A Minson

Christopher T Cummings

Minjung Lee

Trevor G Glaros

Dianne L Newton

Susan Sather

Dehui Zhang

Dmitri Kireev

William P Janzen

H Shelton Earp

Douglas K Graham

Stephen V Frye

Xiaodong Wang

Affiliations

Soon will be listed here.

Abstract

We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

Citing Articles

A feeding-induced myokine modulates glucose homeostasis.

Shi X, Hu X, Fang X, Jia L, Wei F, Peng Y Nat Metab. 2025; 7(1):68-83.

PMID: 39747483 DOI: 10.1038/s42255-024-01175-9.

Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer.

Ayala-Aguilera C, Ge Y, Lorente-Macias A, Jones B, Adam C, Carragher N RSC Med Chem. 2024; .

PMID: 39493221 PMC: 11528321. DOI: 10.1039/d4md00579a.

MERTK Is a Potential Therapeutic Target in Ewing Sarcoma.

Smart S, Yeung T, Santos M, McSwain L, Wang X, Frye S Cancers (Basel). 2024; 16(16).

PMID: 39199601 PMC: 11352666. DOI: 10.3390/cancers16162831.

Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours.

Dave F, Herrera K, Lockley A, van de Weijer L, Henderson S, Sofela A Oncogene. 2024; 43(41):3049-3061.

PMID: 39179860 PMC: 11458476. DOI: 10.1038/s41388-024-03131-z.

MERTK Inhibition as a Targeted Novel Cancer Therapy.

Tanim K, Holtzhausen A, Thapa A, Huelse J, Graham D, Earp H Int J Mol Sci. 2024; 25(14).

PMID: 39062902 PMC: 11277220. DOI: 10.3390/ijms25147660.

References

Diana G, Rudewicz P, Pevear D, Nitz T, Aldous S, Aldous D . Picornavirus inhibitors: trifluoromethyl substitution provides a global protective effect against hepatic metabolism. J Med Chem. 1995; 38(8):1355-71. DOI: 10.1021/jm00008a014. View

Verma A, Warner S, Vankayalapati H, Bearss D, Sharma S . Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011; 10(10):1763-73. DOI: 10.1158/1535-7163.MCT-11-0116. View

Copeland R . Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. Methods Biochem Anal. 2005; 46:1-265. View

Abu-Duhier F, Goodeve A, Wilson G, Gari M, Peake I, Rees D . FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol. 2000; 111(1):190-5. DOI: 10.1046/j.1365-2141.2000.02317.x. View

Schlegel J, Sambade M, Sather S, Moschos S, Tan A, Winges A . MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J Clin Invest. 2013; 123(5):2257-67. PMC: 3639697. DOI: 10.1172/JCI67816. View

Bach R, Dmitrenko O . Strain energy of small ring hydrocarbons. Influence of C-h bond dissociation energies. J Am Chem Soc. 2004; 126(13):4444-52. DOI: 10.1021/ja036309a. View

Schroeder G, An Y, Cai Z, Chen X, Clark C, Cornelius L . Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem. 2009; 52(5):1251-4. DOI: 10.1021/jm801586s. View

Patricelli M, Nomanbhoy T, Wu J, Brown H, Zhou D, Zhang J . In situ kinase profiling reveals functionally relevant properties of native kinases. Chem Biol. 2011; 18(6):699-710. PMC: 3142620. DOI: 10.1016/j.chembiol.2011.04.011. View

Anastassiadis T, Deacon S, Devarajan K, Ma H, Peterson J . Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011; 29(11):1039-45. PMC: 3230241. DOI: 10.1038/nbt.2017. View

10.

Lee-Sherick A, Eisenman K, Sather S, McGranahan A, Armistead P, McGary C . Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia. Oncogene. 2013; 32(46):5359-68. PMC: 3898106. DOI: 10.1038/onc.2013.40. View

11.

Liu J, Zhang W, Stashko M, DeRyckere D, Cummings C, Hunter D . UNC1062, a new and potent Mer inhibitor. Eur J Med Chem. 2013; 65:83-93. PMC: 3720808. DOI: 10.1016/j.ejmech.2013.03.035. View

12.

Zhang W, McIver A, Stashko M, DeRyckere D, Branchford B, Hunter D . Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. J Med Chem. 2013; 56(23):9693-700. PMC: 3962266. DOI: 10.1021/jm4013888. View

13.

Liu J, Wang X . Microwave-assisted, divergent solution-phase synthesis of 1,3,6-trisubstituted pyrazolo[3,4-d]pyrimidines. ACS Comb Sci. 2011; 13(4):414-20. DOI: 10.1021/co200039k. View

14.

Yan S, Peek V, Ajamie R, Buchanan S, Graff J, Heidler S . LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2013; 31(4):833-44. PMC: 3717159. DOI: 10.1007/s10637-012-9912-9. View

15.

Linger R, Keating A, Earp H, Graham D . TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008; 100:35-83. PMC: 3133732. DOI: 10.1016/S0065-230X(08)00002-X. View

16.

Linger R, Lee-Sherick A, DeRyckere D, Cohen R, Jacobsen K, McGranahan A . Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia. Blood. 2013; 122(9):1599-609. PMC: 3757372. DOI: 10.1182/blood-2013-01-478156. View

17.

Schurer S, Muskal S . Kinome-wide activity modeling from diverse public high-quality data sets. J Chem Inf Model. 2012; 53(1):27-38. PMC: 3569091. DOI: 10.1021/ci300403k. View

18.

Greshock J, Bachman K, Degenhardt Y, Jing J, Wen Y, Eastman S . Molecular target class is predictive of in vitro response profile. Cancer Res. 2010; 70(9):3677-86. DOI: 10.1158/0008-5472.CAN-09-3788. View

19.

Liu J, Yang C, Simpson C, DeRyckere D, Van Deusen A, Miley M . Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia. ACS Med Chem Lett. 2012; 3(2):129-134. PMC: 3365829. DOI: 10.1021/ml200239k. View

20.

Howard S, Berdini V, Boulstridge J, Carr M, Cross D, Curry J . Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem. 2009; 52(2):379-88. DOI: 10.1021/jm800984v. View