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Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR., (©2016 American Association for Cancer Research.)

A model system has been developed to explore the relationship between cell cycle arrest and chemotherapeutic toxicity. An isopropyl-1-thio-beta-D-galactopyranoside-inducible P16 construct was introduced stably into a melanoma cell line and used to promote G0-G1 arrest in the recipient cells. The state of arrest was reversible and did not compromise cell viability over a period of at least 7 days. Isopropyl-1-thio-beta-D-galactopyranoside-treated, arrested cells were significantly more resistant to the chemotherapeutic agents methotrexate (approximately 50 times), vinblastine (>100 times), and cisplatin (approximately 10 times) compared to controls. This strategy of protection from chemotherapy exploits one of the basic genotypic differences between normal cells and tumor cells: the integrity of genetic pathways that regulate growth.