Chapeau, Emilie and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ/pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature cancer.

Abstract

The YAP/TEAD protein-protein interaction is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. All current, advanced pharmacological agents which aim at inhibiting YAP/TEAD oncogenic function do so by engaging into the lipid pocket of TEAD. Thereby the consequences of a direct pharmacological disruption of the interface of YAP and TEADs remain largely unexplored. Here we present IAG933, the first molecule able to potently directly disrupt the YAP/TAZ-TEADs protein-protein interaction with suitable properties to enter in clinical trial.

The path to drug discovery was established by careful and systematic analysis of natural sequences of YAP and TAZ binding to TEAD as well as complemented with structure-based optimization of a truncated natural YAP peptide allowing the pharmacophore mapping of the coil binding site of TEAD. Based on in silico screening, confirmed hit was optimized using structure-based and property-based lead optimization yielding IAG933.

Biochemical and cellular assays demonstrated that IAG933 specifically abrogates the interaction between YAP/TAZ coactivators and all four TEAD isoforms, thus inhibiting TEAD-driven transcriptional activity and inducing cancer cell killing. Exquisite compound selectivity was shown in rescue experiments and is consistent with the correlation observed between pharmacological and genetic sensitivity profiles across a large panel of cancer cell lines.

At the epigenomics level, we observe YAP eviction from chromatin and relocation to the cytoplasm upon treatment with IAG933, leaving TEADs genomic occupancy unaffected and consequently competent to engage its co-repressor VGLL4. Concomitantly, we detect a decrease in enhancer activity and accessibility upon loss of YAP occupancy, which translates to rapid and progressive changes in transcription of Hippo target genes.

In preclinical experiments, IAG933 displays linear pharmacokinetics, consistent with dose proportional in vivo TEAD transcriptional inhibition and anti-tumor efficacy in orthotopic and subcutaneous mouse and rat xenograft and primary-tumor derived malignant pleural mesothelioma models. Importantly, IAG933 elicits complete tumor regression in the MSTO-211H xenograft model at doses that were well tolerated in mice and rats. In line with the current clinical strategy for IAG933, we also demonstrate robust anti-tumor efficacy in cancer models bearing NF2 loss of function or expressing TAZ-fusions.

Moreover, we provide evidence for robust combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. This is also consistent with IAG933-induced YAP displacement at AP1/TEAD chromatin-binding sites.

Overall, our results provide a robust rationale of progressing IAG933 as monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat several patient populations of high unmet medical need.

Item Type:	Article
Keywords:	IAG933 PPIi combination therapies
Date Deposited:	09 May 2023 00:45
Last Modified:	09 May 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49234