Abstract
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure–activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC50) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
Highlights
Lysyl oxidase (LOX) and its family members LOX-like (LOXL) 1−4 are copper-dependent amine oxidases that covalently cross-link collagens and elastin in the tumor extracellular matrix.[1−4] LOX is secreted as a catalytically inactive 50 kDa pro-protein, which is cleaved to an active 32 kDa enzyme by proteases such as procollagen C-proteinase
We ran a high-throughput screen (HTS) at Evotec, of 267 000 diverse compounds and 5000 fragments, on LOX, which yielded a hit rate of 0.4%. (5(Piperidin-1-ylsulfonyl)thiophen-2-yl)methanamine 2a was identified as a positive hit with a mean IC50 of 19 μM
Further Structure−activity relationship (SAR) optimization leads to the discovery of inhibitor 9f with potent anti-LOX activity as well as desirable selectivity and PK profile, making it a valuable asset for LOX
Summary
Lysyl oxidase (LOX) and its family members LOX-like (LOXL) 1−4 are copper-dependent amine oxidases that covalently cross-link collagens and elastin in the tumor extracellular matrix.[1−4] LOX is secreted as a catalytically inactive 50 kDa pro-protein, which is cleaved to an active 32 kDa enzyme by proteases such as procollagen C-proteinase. LOX and LOXL1−4 have variable N-termini, and they share a highly conserved C-terminus, where the catalytic domain is located. The catalytic site comprises a copper binding motif and a covalently bound lysine tyrosylquinone (LTQ) cofactor, where peptidyl lysine residues (H2NCH2R) are converted to the corresponding α-aminoadipic-δ-semialdehyde (O CHR) in an oxidative deamination reaction.[3] The newly formed aldehyde residues undergo spontaneous cross-linking with adjacent nucleophilic functionalities, leading to the insoluble extracellular protein matrices. Therapeutic agents targeting the activity of LOX are proposed as cancer treatments, especially against metastasis where no effective therapeutic methods are currently available
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