Fighting fibrosis Improving target selectivity and defining cell phenotypes may improve the odds of finding therapies for fibrosis
only on epithelial cells. Both are scarce in healthy individuals. Pliant synthesized a small molecule, PLN-74809, that blocks these two subtypes by occupying the integrin RGD -binding pockets normally used to activate TGFβ. The result, according to Coulie, is antifibrotic activity “approaching complete TGFβ blocking but limited to fibrotic tissue.”
Unlike Galecto’s GB0139, Pliant’s PLN-74809 didn’t raise any safety concerns when the data-safety monitoring board looked at the ongoing placebo-controlledin February 2022. Instead, the board “allowed us a higher dose level, and longer treatment” duration, says Coulie. Autotaxin catalyzes the conversion of lysophosphatidylcholine to LPA, a signaling lipid that triggers myofibroblast activation and differentiation. LPA is present on both epithelial cells and fibroblasts, working upstream of TGFβ to activate it via integrins, but also activating other pro-fibrotic genes and mediators .
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