<p dir="ltr">In this study, we presented the discovery of the first-in-class covalent inhibitor specific to Src homology 2 domain containing phosphatase 1 (SHP1), an overlooked cancer immunotherapy target. Through high-throughput screening, we identified a chloroacetamide fragment highly selective for SHP1. This fragment was subsequently refined to yield M029, a covalent inhibitor characterized by low-micromolar potency, heightened selectivity, enhanced stability, and improved bioavailability. Notably, M029 targets a cryptic, non-conserved cysteine residue on SHP1, thereby illuminating novel avenues for future drug development focused on SHP1. This presented study also marked the first characterization of SHP1 pharmacology inhibition <i>in vivo</i> using M029 as a tool compound. Consistent to previous genetic studies, SHP1 inhibition was observed to markedly bolster anti-tumor efficacy, primarily through the activation of CD8+ T cells and NK cells, coupled with a reduction in T cell exhaustion. While no synergistic effects were noted in conjunction with anti-PD-1 treatment, M029 as a standalone therapy showcased more favorable responses compared to anti-PD-1 therapy alone, underscoring its potential for clinical application.</p><p dir="ltr">Meanwhile, we also demonstrated the effects of targeting both protein tyrosine phosphatase 1B (PTP1B), and T cell protein tyrosine phosphatase (TC-PTP) using proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional small molecules comprising a targeted protein ligand, an E3 ligase ligand, and a linker. By recruiting an E3 ligase to the targeted proteins, PROTACs leverages the cell's ubiquitin-proteasome machinery to achieve selective target protein degradation. In contrast to traditional occupancy-based inhibitors, event-driven PROTACs show improved efficacy by promoting target protein degradation in a catalytic mode of action and greater selectivity through the obligatory formation of the target-PROTAC-E3 ternary complex, which is essential for efficient target degradation. Through optimizing the previously reported PROTAC DU-14, we acquired a cereblon (CRBN)-based PTP1B/TC-PTP dual targeting PROTAC X1 of higher bioavailability than DU-14. X1 showed enhanced efficacy than DU-14 in multiple cell lines and manifested anti-cancer efficacy <i>in vivo</i>. Additionally, employing X1 as a tool compound, we validated the anti-cancer potential of PTP1B/TC-PTP degradation in STAT3 dependent malignancies, such as non-Hodgkin’s lymphomas. Treatments with X1 or DU-14 effectively induced tumor cell apoptosis, whereas the dual inhibitor ABBV-CLS-484 failed to produce comparable outcomes.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/26207618 |
| Date | 09 July 2024 |
| Creators | Zihan Qu (18990101) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/_b_Targeting_Protein_Tyrosine_Phosphatases_with_Small_Molecules_as_a_Novel_Cancer_Immunotherapy_b_/26207618 |
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