Recently, functional genomics screens using CRISPR/Cas9 technology have demonstrated that knockout of PTPN2 in either tumor cells or T cells leads to improved immune clearance and synergy with anti-PD1 treatment through enhancing IFNγ signaling and T cell receptor signaling, respectively. Thus, small molecule inhibitors of PTPN2 could be useful therapeutics with a unique mechanism for the treatment of cancer.
PTPN2 is a protein tyrosine phosphatase (PTP) that regulates intracellular signaling through dephosphorylation of various substrates. It has historically been challenging to develop orthosteric PTP inhibitors due to the poor druggability of their positively charged phosphotyrosine binding site. Challenges encountered on multiple PTP inhibitor drug discovery campaigns have earned this class of targets a reputation for being “undruggable”.

Through structure-based drug design (SBDD), a benzothiophene difluoromethyl phosphonate (DFMP) series of PTPN1/N2 dual inhibitors was discovered. This series was uniquely potent in cells and demonstrated good tractability. However, the poor physicochemical properties imparted by the negatively charged DFMP functionality presented unique challenges to address, namely, low permeability, extrahepatic clearance and active transport mediated cellular uptake driven by the reduced folate carrier SLC19A1. Key crystallographic insights and synthetic innovations enabled exploration of structure activity relationships across several vectors and the optimization of potency, selectivity, and pharmacokinetics. In parallel to these efforts, a systematic approach to better understand the translational risk posed by transporter activity was taken that involved compound distribution studies and assessment of activity across species and cell types. These efforts resulted in the discovery of compound-1 that demonstrated robust in vivo PK/PD in a MC38 mouse model at low doses when administered subcutaneously. It is anticipated that this high-quality molecule will enable the interrogation of key questions surrounding the targeting of PTPN1/2 with small molecules for cancer immunotherapy.

Mangeng Cheng

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