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Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers.

Lim J, Kelley EH, Methot JL, Zhou H, Petrocchi A, Chen H, Hill SE, Hinton MC, Hruza A, Jung JO, Maclean JK, Mansueto M, Naumov GN, Philippar U, Raut S, Spacciapoli P, Sun D, Siliphaivanh P
J Med Chem 59 6501-11 (2016)
Cited: 9 times
EuropePMC logo PMID: 27329786

Abstract

The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.

Articles - 5ke0 mentioned but not cited (1)

  1. Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy. Zhang L, Ju Q, Sun J, Huang L, Wu S, Wang S, Li Y, Guan Z, Zhu Q, Xu Y. Molecules 25 E5693 (2020)


Reviews citing this publication (5)

  1. Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial-Mesenchymal Transition in Cancer. Olea-Flores M, Zuñiga-Eulogio MD, Mendoza-Catalán MA, Rodríguez-Ruiz HA, Castañeda-Saucedo E, Ortuño-Pineda C, Padilla-Benavides T, Navarro-Tito N. Int J Mol Sci 20 E2885 (2019)
  2. Emerging strategies to target RAS signaling in human cancer therapy. Chen K, Zhang Y, Qian L, Wang P. J Hematol Oncol 14 116 (2021)
  3. Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date. Boespflug A, Caramel J, Dalle S, Thomas L. Ther Adv Med Oncol 9 481-492 (2017)
  4. Conformational control in structure-based drug design. Zheng Y, Tice CM, Singh SB. Bioorg Med Chem Lett 27 2825-2837 (2017)
  5. MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives. Ram T, Singh AK, Kumar A, Singh H, Pathak P, Grishina M, Khalilullah H, Jaremko M, Jaremko M, Emwas AH, Verma A, Kumar P. RSC Med Chem 14 1837-1857 (2023)

Articles citing this publication (3)

  1. Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors. Lechtenberg BC, Mace PD, Sessions EH, Williamson R, Stalder R, Wallez Y, Roth GP, Riedl SJ, Pasquale EB. ACS Med Chem Lett 8 726-731 (2017)
  2. A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases. Miller CJ, Muftuoglu Y, Turk BE. Biochem Pharmacol 142 39-45 (2017)
  3. Tracking binding modes of 1,2,4-trisubstituted imidazolinone P38 MAP kinase and ERK-2 inhibitors. Rao SN. J Mol Graph Model 76 161-171 (2017)


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