Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

Abstract

Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi's [J. Med. Chem.2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem.2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem.2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450's 2C9 and 2C19. Lowering the logD by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.

The nuclear translocation of ERK1/2 as an anticancer target

“…We also compared the effect of the EPE peptide to that of the ERK inhibitor GDC-0994, which is currently in clinical trials 27 ( Supplementary Fig. 10).…”

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

“…Among them, RAF kinases are vitally involved in the phosphorylation and activation of MEK. There are two forms of MEK in humans, including MEK1 and MEK2, which share 79% identical amino acid sequence and have equal ability to phosphorylate specific tyrosine and threonine residues for the downstream target ERK substrates [1][2][3]. Enhanced MEK activity can cause abnormal activation in the RAS-RAF-MEK-ERK pathway, which has been reported to be responsible for the pathogenesis of inflammation and approximately 30% of all human malignancies [4,5].…”

A benzoxazole compound as a novel MEK inhibitor for the treatment of RAS/RAF mutant cancer

“…a ). Previously reported X‐ray structures indicate that there are several key interactions between MEK inhibitors and the MEK allosteric pocket . 1).…”