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Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.

Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Gunzner-Toste J, Zhao G, Yuen PW, Bair KW
J Med Chem 56 4921-37 (2013)
Related entries: 4kfn, 4kfo

Cited: 29 times
EuropePMC logo PMID: 23617784

Abstract

Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).

Articles - 4jr5 mentioned but not cited (2)

  1. Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase. Xu TY, Zhang SL, Dong GQ, Liu XZ, Wang X, Lv XQ, Qian QJ, Zhang RY, Sheng CQ, Miao CY. Sci Rep 5 10043 (2015)
  2. A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma. Zhang S, Mo Z, Zhang S, Li X. Evid Based Complement Alternat Med 2021 8947304 (2021)


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  2. Bifunctional HDAC Therapeutics: One Drug to Rule Them All? Smalley JP, Cowley SM, Hodgkinson JT. Molecules 25 E4394 (2020)
  3. From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases. Zhu Y, Xu P, Huang X, Shuai W, Liu L, Zhang S, Zhao R, Hu X, Wang G. Front Pharmacol 13 920113 (2022)

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  1. Boosting NAD+ with a small molecule that activates NAMPT. Gardell SJ, Hopf M, Khan A, Dispagna M, Hampton Sessions E, Falter R, Kapoor N, Brooks J, Culver J, Petucci C, Ma CT, Cohen SE, Tanaka J, Burgos ES, Hirschi JS, Smith SR, Sergienko E, Pinkerton AB. Nat Commun 10 3241 (2019)
  2. Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models. O'Brien T, Oeh J, Xiao Y, Liang X, Vanderbilt A, Qin A, Yang L, Lee LB, Ly J, Cosino E, LaCap JA, Ogasawara A, Williams S, Nannini M, Liederer BM, Jackson P, Dragovich PS, Sampath D. Neoplasia 15 1314-1329 (2013)
  3. Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT). Zheng X, Bair KW, Bauer P, Baumeister T, Bowman KK, Buckmelter AJ, Caligiuri M, Clodfelter KH, Feng Y, Han B, Ho YC, Kley N, Li H, Liang X, Liederer BM, Lin J, Ly J, O'Brien T, Oeh J, Oh A, Reynolds DJ, Sampath D, Sharma G, Skelton N, Smith CC, Tremayne J, Wang L, Wang W, Wang Z, Wu H, Wu J, Xiao Y, Yang G, Yuen PW, Zak M, Dragovich PS. Bioorg Med Chem Lett 23 5488-5497 (2013)
  4. Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase. Oh A, Ho YC, Zak M, Liu Y, Chen X, Yuen PW, Zheng X, Liu Y, Dragovich PS, Wang W. Chembiochem 15 1121-1130 (2014)
  5. Structural basis for resistance to diverse classes of NAMPT inhibitors. Wang W, Elkins K, Oh A, Ho YC, Wu J, Li H, Xiao Y, Kwong M, Coons M, Brillantes B, Cheng E, Crocker L, Dragovich PS, Sampath D, Zheng X, Bair KW, O'Brien T, Belmont LD. PLoS One 9 e109366 (2014)
  6. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor. Lin W, Yang L, Chai SC, Lu Y, Chen T. Eur J Med Chem 108 505-528 (2016)
  7. Discovery of Novel Inhibitors and Fluorescent Probe Targeting NAMPT. Wang X, Xu TY, Liu XZ, Zhang SL, Wang P, Li ZY, Guan YF, Wang SN, Dong GQ, Zhuo S, Le YY, Sheng CQ, Miao CY. Sci Rep 5 12657 (2015)
  8. Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT). Dragovich PS, Bair KW, Baumeister T, Ho YC, Liederer BM, Liu X, Liu Y, O'Brien T, Oeh J, Sampath D, Skelton N, Wang L, Wang W, Wu H, Xiao Y, Yuen PW, Zak M, Zhang L, Zheng X. Bioorg Med Chem Lett 23 4875-4885 (2013)
  9. Measuring NAD(+) levels in mouse blood and tissue samples via a surrogate matrix approach using LC-MS/MS. Liang X, Yang L, Qin AR, Ly J, Liederer BM, Messick K, Ma S, Zak M, Dragovich PS, Dean BJ, Hop CE, Deng Y. Bioanalysis 6 1445-1457 (2014)
  10. Crystal structure-based comparison of two NAMPT inhibitors. Zhang SL, Xu TY, Yang ZL, Han S, Zhao Q, Miao CY. Acta Pharmacol Sin 39 294-301 (2018)
  11. Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT). Dragovich PS, Zhao G, Baumeister T, Bravo B, Giannetti AM, Ho YC, Hua R, Li G, Liang X, Ma X, O'Brien T, Oh A, Skelton NJ, Wang C, Wang W, Wang Y, Xiao Y, Yuen PW, Zak M, Zhao Q, Zheng X. Bioorg Med Chem Lett 24 954-962 (2014)
  12. Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility. Zak M, Liederer BM, Sampath D, Yuen PW, Bair KW, Baumeister T, Buckmelter AJ, Clodfelter KH, Cheng E, Crocker L, Fu B, Han B, Li G, Ho YC, Lin J, Liu X, Ly J, O'Brien T, Reynolds DJ, Skelton N, Smith CC, Tay S, Wang W, Wang Z, Xiao Y, Zhang L, Zhao G, Zheng X, Dragovich PS. Bioorg Med Chem Lett 25 529-541 (2015)
  13. Identification of benzothiophene amides as potent inhibitors of human nicotinamide phosphoribosyltransferase. Chen W, Dong G, He S, Xu T, Wang X, Liu N, Zhang W, Miao C, Sheng C. Bioorg Med Chem Lett 26 765-768 (2016)
  14. Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors. Tanuma SI, Katsuragi K, Oyama T, Yoshimori A, Shibasaki Y, Asawa Y, Yamazaki H, Makino K, Okazawa M, Ogino Y, Sakamoto Y, Nomura M, Sato A, Abe H, Nakamura H, Takahashi H, Tanuma N, Uchiumi F. Molecules 25 E3633 (2020)
  15. Structure-Guided Design and In-Cell Target Profiling of a Cell-Active Target Engagement Probe for PARP Inhibitors. Howard RT, Hemsley P, Petteruti P, Saunders CN, Molina Bermejo JA, Scott JS, Johannes JW, Tate EW. ACS Chem Biol 15 325-333 (2020)
  16. Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors. Zheng X, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Wang Y, Yuen PW, Bair KW. Bioorg Med Chem Lett 24 337-343 (2014)
  17. Machine Learning Models for the Prediction of Chemotherapy-Induced Peripheral Neuropathy. Bloomingdale P, Mager DE. Pharm Res 36 35 (2019)
  18. SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT). Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, Michaelides MR. Bioorg Med Chem Lett 27 3317-3325 (2017)
  19. Small Molecule Regulators Targeting NAD+ Biosynthetic Enzymes. Curry A, White D, Cen Y. Curr Med Chem 29 1718-1738 (2022)
  20. Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators. Tang S, Garzon Sanz M, Smith O, Krämer A, Egbase D, Caton PW, Knapp S, Butterworth S. Acta Pharm Sin B 13 709-721 (2023)
  21. Identification of novel Nicotinamide Phosphoribosyltransferase (NAMPT) inhibitors using computational approaches. Kesherwani M, Raghavan S, Gunasekaran K, Velmurugan D. J Biomol Struct Dyn 36 1306-1328 (2018)
  22. Enhanced mapping of small-molecule binding sites in cells. Wozniak JM, Li W, Governa P, Chen LY, Jadhav A, Dongre A, Forli S, Parker CG. Nat Chem Biol (2024)
  23. Novel carbon skeletons activate human NicotinAMide Phosphoribosyl Transferase (NAMPT) enzyme in biochemical assay. Almeida KH, Avalos-Irving L, Berardinelli S, Chauvin K, Yanez S. PLoS One 18 e0283428 (2023)
  24. Synthesis of Novel Hybrids Inspired from Bromopyrrole Alkaloids Inhibiting MMP-2 and -12 as Antineoplastic Agents. Rane RA, Naphade SS, Bangalore PK, Palkar MB, Patel HM, Shaikh MS, Alwan WS, Karpoormath R. Chem Biol Drug Des 86 210-222 (2015)


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