Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors

Abstract

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1–18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 may stem from noncovalent interactions like hydrogen bonding between the morpholine/piperazine rings with the LH2-specific Arg661. Treatment of 344SQ WT cells with 13 resulted in a dose-dependent reduction in their migration potential, whereas the compound did not impede the migration of the same cell line with an LH2 knockout (LH2KO).

Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

“…Due to strong evidence for dysregulated ECM crosslinking in promoting fibrosis and the key roles of ECM crosslinking enzymes, therapeutics are actively being investigated to target TG, LOX, and LH proteins, with the most advanced drug molecules in phase I/II clinical trials ( Table 1 ) [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. LOX therapeutics vary based on which LOX they target, and both small-molecule and antibody-based targeting approaches have been employed.…”

“…The most advanced anti-TG2 antibody, Zampilimab, is in clinical trials for adult kidney transplant patients with chronic allograft injury, with potential follow up interest in fibrotic diseases (NCT04335578). For targeting LH2, small-molecule inhibitors have been discovered and proposed for use in fibrosis and cancer metastasis [ 90 , 91 , 92 ]. Overall, significant efforts are being made to develop novel therapeutics targeting crosslinking for fibrosis treatment.…”

Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

“…It is noteworthy that inhibitory antibodies have also been discovered to target TG2 [84,85].The most advanced anti-TG2 antibody, Zampilimab, is in clinical trials for adult kidney transplant patients with chronic allograft injury, with potential follow-up interest in fibrotic diseases (NCT04335578). For targeting LH2, small-molecule inhibitors have been discovered and proposed for use in fibrosis and cancer metastasis [90][91][92]. Overall, significant efforts are being made to develop novel therapeutics targeting crosslinking for fibrosis treatment.…”

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

“…Recently, it has been reported that Lh2-mediated extracellular matrix remodeling promotes invasiveness and metastasis in an orthotopic xenograft mice model [ 105 ]. Finally, specific inhibitors of Lh2 have been isolated and display antimigratory activity in vitro [ 106 ], although their efficacy has not yet been demonstrated in vivo.…”