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Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors.

Morgan CA, Hurley TD
J Med Chem 58 1964-75 (2015)
Related entries: 4wp7, 4wpn

Cited: 36 times
EuropePMC logo PMID: 25634381

Abstract

Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson's disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit submicromolar inhibition constants but have different mechanisms of inhibition. The crystal structures of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique glycine residue to achieve their selectivity. These two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states.

Reviews - 4x4l mentioned but not cited (1)

  1. Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer. Xanthis V, Mantso T, Dimtsi A, Pappa A, Fadouloglou VE. Cancers (Basel) 15 4419 (2023)

Articles - 4x4l mentioned but not cited (4)

  1. Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors. Morgan CA, Hurley TD. J Med Chem 58 1964-1975 (2015)
  2. Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy. Huddle BC, Grimley E, Buchman CD, Chtcherbinine M, Debnath B, Mehta P, Yang K, Morgan CA, Li S, Felton J, Sun D, Mehta G, Neamati N, Buckanovich RJ, Hurley TD, Larsen SD. J Med Chem 61 8754-8773 (2018)
  3. Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent. Dinavahi SS, Gowda R, Gowda K, Bazewicz CG, Chirasani VR, Battu MB, Berg A, Dokholyan NV, Amin S, Robertson GP. Mol Cancer Ther 19 447-459 (2020)
  4. N-Substituted 2-(Benzenosulfonyl)-1-Carbotioamide Derivatives Exert Antimicrobial and Cytotoxic Effects via Aldehyde Dehydrogenase Pathway: Synthesis, In Silico and In Vitro Studies. Walczak-Nowicka L, Biernasiuk A, Ziemichód W, Karczmarzyk Z, Kwaśnik M, Kozyra P, Wysocki W, Stenzel-Bembenek A, Kowalczuk D, Herbet M, Pitucha M. Pharmaceuticals (Basel) 16 1706 (2023)


Reviews citing this publication (5)

  1. Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies. Muralikrishnan V, Hurley TD, Nephew KP. Cancers (Basel) 12 E961 (2020)
  2. Aldehyde dehydrogenase in regulatory T-cell development, immunity and cancer. Bazewicz CG, Dinavahi SS, Schell TD, Robertson GP. Immunology 156 47-55 (2019)
  3. Advances in Activity-Based Sensing Probes for Isoform-Selective Imaging of Enzymatic Activity. Gardner SH, Reinhardt CJ, Chan J. Angew Chem Int Ed Engl 60 5000-5009 (2021)
  4. Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets. Xia J, Li S, Liu S, Zhang L. MedComm (2020) 4 e195 (2023)
  5. Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer. Colombo G, Gelardi ELM, Balestrero FC, Moro M, Travelli C, Genazzani AA. Front Pharmacol 12 758320 (2021)

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  2. Identification and characterization of antibacterial compound(s) of cockroaches (Periplaneta americana). Ali SM, Siddiqui R, Ong SK, Shah MR, Anwar A, Heard PJ, Khan NA. Appl Microbiol Biotechnol 101 253-286 (2017)
  3. Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity. Yang SM, Martinez NJ, Yasgar A, Danchik C, Johansson C, Wang Y, Baljinnyam B, Wang AQ, Xu X, Shah P, Cheff D, Wang XS, Roth J, Lal-Nag M, Dunford JE, Oppermann U, Vasiliou V, Simeonov A, Jadhav A, Maloney DJ. J Med Chem 61 4883-4903 (2018)
  4. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1). Yang SM, Yasgar A, Miller B, Lal-Nag M, Brimacombe K, Hu X, Sun H, Wang A, Xu X, Nguyen K, Oppermann U, Ferrer M, Vasiliou V, Simeonov A, Jadhav A, Maloney DJ. J Med Chem 58 5967-5978 (2015)
  5. Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK, Schönbrunn E. ACS Chem Biol 13 582-590 (2018)
  6. Family-Four Aldehyde Dehydrogenases Play an Indispensable Role in the Pathogenesis of Magnaporthe oryzae. Abdul W, Aliyu SR, Lin L, Sekete M, Chen X, Otieno FJ, Yang T, Lin Y, Norvienyeku J, Wang Z. Front Plant Sci 9 980 (2018)
  7. Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives. Buchman CD, Hurley TD. J Med Chem 60 2439-2455 (2017)
  8. ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer. Choi JA, Kwon H, Cho H, Chung JY, Hewitt SM, Kim JH. Cancers (Basel) 11 E1553 (2019)
  9. Alternative Biotransformation of Retinal to Retinoic Acid or Retinol by an Aldehyde Dehydrogenase from Bacillus cereus. Hong SH, Ngo HP, Nam HK, Kim KR, Kang LW, Oh DK. Appl Environ Microbiol 82 3940-3946 (2016)
  10. Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1. Feng Z, Hom ME, Bearrood TE, Rosenthal ZC, Fernández D, Ondrus AE, Gu Y, McCormick AK, Tomaske MG, Marshall CR, Kline T, Chen CH, Mochly-Rosen D, Kuo CJ, Chen JK. Nat Chem Biol 18 1065-1075 (2022)
  11. Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues. Koch MF, Harteis S, Blank ID, Pestel G, Tietze LF, Ochsenfeld C, Schneider S, Sieber SA. Angew Chem Int Ed Engl 54 13550-13554 (2015)
  12. Dysregulated Tear Film Proteins in Macular Edema Due to the Neovascular Age-Related Macular Degeneration Are Involved in the Regulation of Protein Clearance, Inflammation, and Neovascularization. Winiarczyk M, Winiarczyk D, Michalak K, Kaarniranta K, Adaszek Ł, Winiarczyk S, Mackiewicz J. J Clin Med 10 3060 (2021)
  13. Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells. Koenders STA, Wijaya LS, Erkelens MN, Bakker AT, van der Noord VE, van Rooden EJ, Burggraaff L, Putter PC, Botter E, Wals K, van den Elst H, den Dulk H, Florea BI, van de Water B, van Westen GJP, Mebius RE, Overkleeft HS, Le Dévédec SE, van der Stelt M. ACS Cent Sci 5 1965-1974 (2019)
  14. Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors. Ibrahim AIM, Ikhmais B, Batlle E, AbuHarb WK, Jha V, Jaradat KT, Jiménez R, Pequerul R, Parés X, Farrés J, Pors K. Molecules 26 5770 (2021)
  15. Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes. Harper AR, Le AT, Mather T, Burgett A, Berry W, Summers JA. Bioorg Med Chem 26 5766-5779 (2018)
  16. Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy. Huddle BC, Grimley E, Chtcherbinine M, Buchman CD, Takahashi C, Debnath B, McGonigal SC, Mao S, Li S, Felton J, Pan S, Wen B, Sun D, Neamati N, Buckanovich RJ, Hurley TD, Larsen SD. Eur J Med Chem 211 113060 (2021)
  17. Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer. Ibrahim AIM, Batlle E, Sneha S, Jiménez R, Pequerul R, Parés X, Rüngeler T, Jha V, Tuccinardi T, Sadiq M, Frame F, Maitland NJ, Farrés J, Pors K. J Med Chem 65 3833-3848 (2022)
  18. Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases. Llorach-Pares L, Nonell-Canals A, Avila C, Sanchez-Martinez M. Mar Drugs 20 53 (2022)
  19. Evaluation of spice and herb as phyto-derived selective modulators of human retinaldehyde dehydrogenases using a simple in vitro method. Bui TBC, Nosaki S, Kokawa M, Xu Y, Kitamura Y, Tanokura M, Hachimura S, Miyakawa T. Biosci Rep 41 BSR20210491 (2021)
  20. Spheroid culture models adequately imitate distinctive features of the renal cancer or melanoma microenvironment. Filipiak-Duliban A, Brodaczewska K, Majewska A, Kieda C. In Vitro Cell Dev Biol Anim 58 349-364 (2022)
  21. Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression. Ge X, Li M, Song GX, Zhang Z, Yin J, Ge Z, Shi Z, Liu LZ, Jiang BH, Qian X, Shen H. Clin Transl Med 12 e1136 (2022)
  22. Identifying candidate reference chemicals for in vitro testing of the retinoid pathway for predictive developmental toxicity. Baker NC, Pierro JD, Taylor LW, Knudsen TB. ALTEX 40 217–236 (2023)
  23. Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of β-Adrenergic Agonists. Ikhmais BA, Hammad AM, Abusara OH, Hamadneh L, Abumansour H, Abdallah QM, Ibrahim AIM, Elsalem L, Awad M, Alshehada R. Curr Issues Mol Biol 45 7996-8012 (2023)
  24. Differentially expressed genes in heads and tails of Angelica sinensis diels: Focusing on ferulic acid metabolism. Yang J, Li WH, An R, Wang YL, Xu Y, Chen J, Wang XF, Zhang XB, Li J, Ding WJ. Chin J Integr Med 23 779-785 (2017)
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