Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry

Abstract

The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.

Improved Diazo-Transfer Reaction for DNA-Encoded Chemistry and Its Potential Application for Macrocyclic DEL-Libraries

“…The next step was to carry out a proof-of-concept study using our method in producing macrocycles attached to DNA as illustrated in Scheme 2. The first step was to selectively convert an amine (5) to its corresponding azide (6) and then carry out an intramolecular [3 + 2]-cycloaddition with an alkyne attached to the DNA to give the macrocycle (7). The [3 + 2]-cycloaddition has previously been used for synthesizing macrocyclic DEL peptide libraries containing 4-20 natural amino acids [26].…”

“…This complete process has been excellently reviewed and described previously [1][2][3][4][5]. The DEL lead finding strategy has been successfully implied to identify clinical candidates like RIP1 kinase inhibitor GSK3145095 [6] and more recently the autotaxin inhibitor X-165 [7].…”

Microarrays and NGS for Drug Discovery

“…In another study, Reidenbach et al attempted to identify compounds against Prion disease, a neurodegenerative disease with no therapeutic options; however, the only benzimidazole compounds identified demonstrated low affinities [196]. Whereas, Cuozzo et al screened a DECL library of 225 million compounds, and identified a single compound (X-165) with a high activity against the production of lysophosphatidic acid, and this compound has been approved by the FDA for Phase I Clinical trials [197]. In other examples of using this strategy, Dawadi et al discovered a thrombin inhibitor using DECL [198], while, Kung et al identified two compounds that presented inhibition/binders to e Nα-terminal acetyltransferase (Naa50) using ECL library screening [199].…”

Employing Photocatalysis for the Design and Preparation of DNA‐Encoded Libraries: A Case Study

“…In recent years, numerous successful DEL selection campaigns have been reported, validating DNA‐encoded libraries as a bona fide hit identification platform for drug discovery. Among the enzyme inhibitors that originated from DELs are ligands against soluble epoxide hydrolase (sEH), [29] interleukin‐2 (IL‐2), [30] receptor interacting protein 1 (RIP1) kinase, [31] metalloprotease ADAMTS‐4, [32] neurokinin 3 (NK3) receptor, [33] discoidin domain receptor 1 (DDR1), [34] autotaxin, [35] thrombin, [36] and N ‐α‐acetyltransferase 50 (Naa50) [37] . This validation, along with the economic attractiveness of this technology, has garnered much attention from the pharmaceutical industry and academic research groups alike.…”