Targeting Oxidized PTP1B for Anticancer Drug Discovery

PROJECT SUMMARY
PTP1B, a non-receptor–type oncogenic PTP, also known as PTPN1, is involved in growth factor signaling. The PTP1B
gene is frequently amplified in cancers and correlates with poor prognosis. However, despite the attractiveness of
PTP1B as a therapeutic target, the development of drug-like inhibitors of this enzyme has proven difficult, primarily
due to low cell permeability and a lack of selectivity towards other PTPs. While numerous investigators are developing
traditional types of inhibitors that target the reduced, active form of PTP1B, targeting PTP1B-ox has important
advantages relating to inhibitor bioavailability and selectivity. The goal of this proposal is to develop charge neutral
inhibitors that specifically target the oxidized form of PTP1B (PTP1B-ox), which exists principally in the disease state.
This approach was validated in a recent study showing that single-chain variable fragment antibodies can stabilize
oxPTP1B and, in so doing, modulate signaling pathways related to energy metabolism and cancer. In Aim 1, we will
prepare and evaluate diverse sulfenic acid-reactive combinatorial libraries. In Aim 2, we will screen libraries prepared
in Aim 1 to identify compounds that target oxidized PTP1B. Based on our expertise in targeting distinct redox forms
of therapeutically important proteins and innovative chemistry (Nat. Chem. Biol. 2012, 2018, 2023 and Nat. Chem.
2021), we will almost certainly identify molecules that target and stabilize the oxidized form of PTP1B. These
nucleophilic compounds will lay the foundation for future studies on this topic as an R21 proposal to examine potency
and SAR in cellular assays.

Grant Number: 5R03CA289646-03
NIH Institute/Center: NIH
Principal Investigator: Kate Carroll