Discovery of (S)‑1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl‑1H‑pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)‑one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

• Published in: Journal of medicinal chemistry Vol. 59; no. 12; pp. 5650 - 5660
• Main Authors: Blake, James F, Burkard, Michael, Chan, Jocelyn, Chen, Huifen, Chou, Kang-Jye, Diaz, Dolores, Dudley, Danette A, Gaudino, John J, Gould, Stephen E, Grina, Jonas, Hunsaker, Thomas, Liu, Lichuan, Martinson, Matthew, Moreno, David, Mueller, Lars, Orr, Christine, Pacheco, Patricia, Qin, Ann, Rasor, Kevin, Ren, Li, Robarge, Kirk, Shahidi-Latham, Sheerin, Stults, Jeffrey, Sullivan, Francis, Wang, Weiru, Yin, Jianping, Zhou, Aihe, Belvin, Marcia, Merchant, Mark, Moffat, John, Schwarz, Jacob B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.06.2016; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; cancer; Cell Proliferation - drug effects; Chemistry, Medicinal; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; inhibitors; Life Sciences & Biomedicine; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; peptides and proteins; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; rodent models; Science & Technology; selectivity; Structure-Activity Relationship; POTENT; STRUCTURE-GUIDED DESIGN; ERK2; 1ST GLOBAL APPROVAL; SMALL-MOLECULE INHIBITORS; RAF; ACQUIRED-RESISTANCE; CASCADE; BRAF; CANCER
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00389

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.