The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once-or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile.
Histone demethylase
LSDl (KDMlA) belongs to the flavin adenine
dinucleotide (FAD) dependent family of monoamine oxidases and is vital
in regulation of mammalian biology. Dysregulation and overexpression
of LSD1 are hallmarks of a number of human diseases, particularly
cancers that are characterized as morphologically poorly differentiated.
As such, inhibitors of LSD1 have potential to be beneficial as a cancer
therapy. The most clinically advanced inhibitors of LSDl are covalent
inhibitors derived from tranylcypromine (TCP). Herein, we report the
discovery of a novel series of reversible and selective LSDl inhibitors.
Exploration of structure–activity relationships (SARs) and
optimization of ADME properties resulted in the identification of
clinical candidate CC-90011. CC-90011 exhibits potent on-target induction
of cellular differentiation in acute myeloid leukemia (AML) and small
cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived
xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials
in patients with first line, extensive stage SCLC (ClinicalTrials.gov
identifier: NCT03850067).
Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.
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