Incorporation of Metabolically Stable Ketones into a Small Molecule Probe to Increase Potency and Water Solubility

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2015 Aug 2

PMID 26231156

Citations 58

Authors

Marie-Helene Larraufie

Wan Seok Yang

Elise Jiang

Ajit G Thomas

Barbara S Slusher

Brent R Stockwell

Affiliations

Soon will be listed here.

Abstract

Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications.

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References

Kwarcinski F, Fox C, Steffey M, Soellner M . Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine. ACS Chem Biol. 2012; 7(11):1910-7. PMC: 3500393. DOI: 10.1021/cb300337u. View

Lee C, Grossmann T . Reversible covalent inhibition of a protein target. Angew Chem Int Ed Engl. 2012; 51(35):8699-700. DOI: 10.1002/anie.201203341. View

Tomasio S, Harding H, Ron D, Cross B, Bond P . Selective inhibition of the unfolded protein response: targeting catalytic sites for Schiff base modification. Mol Biosyst. 2013; 9(10):2408-16. DOI: 10.1039/c3mb70234k. View

Ward R, Anderton M, Ashton S, Bethel P, Box M, Butterworth S . Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J Med Chem. 2013; 56(17):7025-48. DOI: 10.1021/jm400822z. View

Mah R, Thomas J, Shafer C . Drug discovery considerations in the development of covalent inhibitors. Bioorg Med Chem Lett. 2013; 24(1):33-9. DOI: 10.1016/j.bmcl.2013.10.003. View

Yang W, Sriramaratnam R, Welsch M, Shimada K, Skouta R, Viswanathan V . Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014; 156(1-2):317-331. PMC: 4076414. DOI: 10.1016/j.cell.2013.12.010. View

Wu H, Wang W, Liu F, Weisberg E, Tian B, Chen Y . Discovery of a potent, covalent BTK inhibitor for B-cell lymphoma. ACS Chem Biol. 2014; 9(5):1086-91. PMC: 4027949. DOI: 10.1021/cb4008524. View

Dixon S, Patel D, Welsch M, Skouta R, Lee E, Hayano M . Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014; 3:e02523. PMC: 4054777. DOI: 10.7554/eLife.02523. View

Lanning B, Whitby L, Dix M, Douhan J, Gilbert A, Hett E . A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. Nat Chem Biol. 2014; 10(9):760-767. PMC: 4138289. DOI: 10.1038/nchembio.1582. View

10.

Dolma S, Lessnick S, Hahn W, Stockwell B . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003; 3(3):285-96. DOI: 10.1016/s1535-6108(03)00050-3. View

11.

Barbas 3rd C, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjornestedt R . Immune versus natural selection: antibody aldolases with enzymic rates but broader scope. Science. 1998; 278(5346):2085-92. DOI: 10.1126/science.278.5346.2085. View

12.

Cohen M, Zhang C, Shokat K, Taunton J . Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005; 308(5726):1318-21. PMC: 3641834. DOI: 10.1126/science1108367. View

13.

Conklin D, Prough R, Bhatanagar A . Aldehyde metabolism in the cardiovascular system. Mol Biosyst. 2007; 3(2):136-50. DOI: 10.1039/b612702a. View

14.

Li W, Sperry J, Crowe A, Trojanowski J, Smith 3rd A, Lee V . Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem. 2009; 110(4):1339-51. PMC: 2758489. DOI: 10.1111/j.1471-4159.2009.06224.x. View

15.

Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro S . A structure-guided approach to creating covalent FGFR inhibitors. Chem Biol. 2010; 17(3):285-95. PMC: 2920453. DOI: 10.1016/j.chembiol.2010.02.007. View

16.

Singh J, Petter R, Baillie T, Whitty A . The resurgence of covalent drugs. Nat Rev Drug Discov. 2011; 10(4):307-17. DOI: 10.1038/nrd3410. View

17.

Isom D, Castaneda C, Cannon B, Garcia-Moreno B . Large shifts in pKa values of lysine residues buried inside a protein. Proc Natl Acad Sci U S A. 2011; 108(13):5260-5. PMC: 3069169. DOI: 10.1073/pnas.1010750108. View

18.

Papandreou I, Denko N, Olson M, Van Melckebeke H, Lust S, Tam A . Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood. 2010; 117(4):1311-4. PMC: 3056474. DOI: 10.1182/blood-2010-08-303099. View

19.

Ma Y, Xu B, Fang Y, Yang Z, Cui J, Zhang L . Synthesis and SAR study of novel peptide aldehydes as inhibitors of 20S proteasome. Molecules. 2011; 16(9):7551-64. PMC: 6264673. DOI: 10.3390/molecules16097551. View

20.

Zhang T, Inesta-Vaquera F, Niepel M, Zhang J, Ficarro S, Machleidt T . Discovery of potent and selective covalent inhibitors of JNK. Chem Biol. 2012; 19(1):140-54. PMC: 3270411. DOI: 10.1016/j.chembiol.2011.11.010. View