PY-60 is a novel activator of YAP-dependent gene expression.It targets ANXA2 in the Hippo pathway. PY-60 targets ANXA2 to activate YAP[1]. PY-60, a thiazole-substituted derivative, dose-dependently induces luciferase activity in 293A-TEAD-LUC cells in the presence or absence of serum when cells were plated at high cell density (EC50= 1.5 and 1.6 µM, respectively). PY-60 treatment also dose-dependently promoted the association of YAP and TEAD proteins in cells and induced the nuclear localization of YAP in response to increased cell density. PY-60 robustly increases the levels of YAP-controlled transcripts (that is, ANRKD1, CYR61 and CTGF) in 293A cells and other human cell lines (that is, MCF10A, HEK293T, H69 and HaCaT), but did not augment the levels of YAP itself (YAP1)[1]. PY-60 activates a proproliferative, YAP-dependent transcriptional program in the adult animal capable of remodeling the epidermis through proliferation[1]. PY-60 liberates the ANXA2-YAP complex from the cell membrane and competes for ANXA2 binding of phosphoinositides[1]. PY-60 (10 uM; applied topically to the dorsal skin of wild-type adult C57BL/6 mice over the course of 10 days) promotes a dramatic expansion of keratinocytes and K14-positive precursors, as assessed by hematoxylin and eosin and anti-K14 histological staining at the study end. PY-60 results in an approximate doubling of epidermal thickness, a result derived from an increased number of keratinocytes per unit length of skin[1].

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[1]. Shalhout SZ, et al. YAP-dependent proliferation by a small molecule targeting annexin A2. Nat Chem Biol. 2021;17(7):767-775.