In Vivo Efficacy of Natural Product‐Inspired Irreversible Kinase Inhibitors

Abstract

Hypothemycin and related resorcylic acid lactones (RAL) bearing a cis-enone moiety have emerged as an alternative pharmacophore to heterocyclic motifs for kinase inhibition, and are endowed with a unique selectivity filter based on the irreversible reaction with a subset of the kinome bearing a suitably positioned cysteine residue. Two prototypical examples of "edited" RAL were evaluated for antitumoral, antimetastatic and antiangiogenic efficacy in an orthotopic murine renal cell carcinoma (RENCA) model. Both compounds (3 and 5) are good inhibitors of VEGFRs in vitro, and inhibited tumor growth in vivo with comparable efficacy to sunitinib, an FDA-approved VEGFRs inhibitor. Compound 3 promoted lung metastasis to a similar extent as sunitinib, while compound 5 strongly inhibited lung metastasis. This study attests to the potential of irreversible kinase inhibitors and molecular editing of natural pharmacophores and provides encouraging results to a clinically significant problem.

Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei

“…Hypothemycin (Tanaka et al, 1999) and related compounds (Barluenga et al, 2010) have antitumor activity in mouse xenograft models, and one variant has entered clinical trials (Kumar et al, 2011). All hypothemycin-sensitive kinases have a common cysteine immediately preceding the catalytic DXG motif (where X is usually Phe or Leu) (Schirmer et al, 2006).…”

Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core

“…We then investigated an alternative route in which substituted maleimides were prepared by cyclisation of a maleic monoamide (Scheme 4), 46 which proved to be successful in our synthesis. For example, maleic acid monoamides 47 were obtained by ring-opening amidation of maleic anhydride with amines (35,(37)(38)(39)(40)(41)(45)(46). The monoamide intermediates were then subjected to ring-closing dehydration in refluxing acetic anhydride to provide the maleimides 12, accompanied by O-acetylation of the 2-phenolic group.…”

“…35 It is known that some of these cis-enone RALs such as L-783,277, LL-Z1640-2, hypothemycin and their synthetic analogues are potent inhibitors of FLT3 kinases. [35][36][37][38] However, the synthetic routes to these natural products are lengthy and require the installation of stereogenic centres. In addition, the cis-enone moiety present in these molecules is prone to isomerisation to the less active trans-form.…”

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

“…The fungal natural product hypothemycin [27] and related macrocycles [28] are known to covalently inhibit a subset of human kinases with a cysteine preceding the kinase DXG motif (Fig. 2C,D ).…”