Phosphatase Focused Library

Phosphate groups are known to belong to post-translational protein modifications. Phosphorylation-mediated signaling events regulate many medical conditions, including cancers, neurological diseases, diabetes, pain, autoimmune disorders, and cardiovascular diseases. The modifying enzymes involved, such as phosphorylases and phosphatases, are in the focus of modern drug discovery, aimed at further improvement of public health.

The Life Chemicals cheminformatics team has developed a proprietary Phosphatase Focused Library with a 2D fingerprint similarity search method against reference compound sets from several databases of bioactive molecules. This Screening Set contains over 6,100 potential phosphatase inhibitors for new HTS drug discovery projects focused on phosphatase-related drug discovery and consists of two parts:

• Phosphatase Focused Library - Part I (Similarity search against ChEBIDB, PubChem, DrugBank databases)
• Phosphatase Focused Library - Part II (Similarity search against ChEMBL DB)

Additionally, Protein Tyrosine Phosphatase Non-receptor Type (PTPN) Screening Library of over 800 drug-like screening compounds was developed.

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Figure 1. Kinases catalyze protein phosphorylation (A) and phosphatases catalyze its de-phosphorylation (B). The picture is adopted from Seok, 2011 [1].

Phosphatase Focused Library - Part I

(Similarity search against ChEBI-DB, PubChem, DrugBank databases)

Our similarity search was performed using a reference set of known 12,516 biologically active compounds (Activity (IC₅₀, etc) ≤ 1 µM by PubChem), with their potency in respect of the following 59 phosphatase-related targets being proven in 88 assays (ChEBI-DBs, PubChem, DrugBank databases):

The Life Chemicals HTS Compound Collection was searched for small molecules similar to the compounds included in the reference database, using MDL public keys and the Tanimoto similarity cut-off of 85 % (Fig. 2). Ro5 compliance is indicated; reactive, toxic, or PAINS compounds are excluded from the Library. As a result, over 450 drug-like screening compounds were identified and added to the Screening Library.

Figure 2. Example of representative analogues of the Phosphatase Screening Library selected based on the reference compound set.

Phosphatase Focused Library - Part II

(Similarity search against ChEMBL DB)

The compound reference set of 3,395 unique reported phosphatase inhibitors were prepared based on ChEMBL database entries, following the accepted maximum activity value (IC₅₀ < 1 uM). Subsequently, a similarity search, using 2D fingerprints, generated with the Unity module of Sybyl-X, was applied to the reference set (Tanimoto similarity cut-off of 85 %).

This enabled us to identify and add to the Screening Set almost 5,650 close analogs of known phosphatase binders targeting the following phosphatases:

Representative compounds from Phosphatase Focused Library

F0526-0410

F0373-1190

F0373-0982

F1219-0368

F0372-0938

F3375-1778

F1284-0322

F2542-0764

F1284-0303

F3124-0344

F1284-0337

F0341-0530

F3237-0130

F0373-1083

F3096-3000

F3222-3021

F3222-3020

F0526-0597

Protein Tyrosine Phosphatase Non-receptor Type (PTPN) Screening Library

It has been found that protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation (to remove a phosphate group attached to a tyrosine residue) using a cysteinyl-phosphate enzyme intermediate. Imbalance in signal pathways mediated by these tyrosine-specific protein phosphatases has been associated with the development of many human diseases including cancer, metabolic, and immunological diseases. 

Intracellular non-receptor PTPs (PTPNs), which belong to the largest class I cysteine PTP family, are essential for the regulation of a variety of biological processes, including tumorigenesis, immune system, inflammatory response, and glucose homeostasis. 

Inhibitors of PTPNs have promising applications due to their striking efficacy in antitumor therapy [2]. For instance, it has been shown that protein tyrosine phosphatase non-receptor type 2 (PTPN2) plays a pivotal role in immune homeostasis and has been associated with human autoimmune and chronic inflammatory diseases [3]. Meanwhile, non-receptor protein tyrosine phosphatase SHP2 is a critical component of RAS/MAPK signaling by acting upstream of RAS to promote oncogenic signaling and tumor growth, which makes it a compelling target for anticancer drug discovery [4].

Our cheminformatics team has developed this new Screening Set of over 800 screening molecules using a 2D fingerprint similarity search. The resulting compound selection is compliant with in-house medicinal chemistry filters (PAINS and toxicophore filters, the Rule of Five restrictions). The compound distribution by the protein target is shown in Fig. 3.

Figure 3. Compound distribution targeting tyrosine-protein phosphatase non-receptor type.

References:

1. Seok, S.-H. Structural Insights into Protein Regulation by Phosphorylation and Substrate Recognition of Protein Kinases/Phosphatases. Life 2021, 11, 957. https://doi.org/10.3390/life11090957
2. Tang X, Qi C, Zhou H, Liu Y. Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy. Front Oncol. 2022 Jul 26;12:972906. doi: 10.3389/fonc.2022.972906. PMID: 35957898; PMCID: PMC9360549.
3. Hering L, Katkeviciute E, Schwarzfischer M, Busenhart P, Gottier C, Mrdjen D, Komuczki J, Wawrzyniak M, Lang S, Atrott K, Becher B, Rogler G, Scharl M, Spalinger MR. Protein Tyrosine Phosphatase Non-Receptor Type 2 Function in Dendritic Cells Is Crucial to Maintain Tissue Tolerance. Front Immunol. 2020 Aug 18;11:1856. doi: 10.3389/fimmu.2020.01856. PMID: 32973765; PMCID: PMC7462014.
4. Chou YT, Bivona TG. Inhibition of SHP2 as an approach to block RAS-driven cancers. Adv Cancer Res. 2022;153:205-236. doi: 10.1016/bs.acr.2021.07.002. Epub 2021 Aug 3. PMID: 35101231.