Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB

Abstract

Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of “flatland”, we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website: http://www.icoa.fr/pkidb.

Druggable Transient Pockets in Protein Kinases

“…For the discovery of drugs targeting kinases, identifying type II and III inhibitors has remained quite difficult, and most clinically approved kinase inhibitors are type I [ 45 ]. Thus, alternative systematic and straightforward approaches for identifying type II and III inhibitors have been pursued.…”

KLIFS: an overhaul after the first 5 years of supporting kinase research

“…This new page provides an overview of drugs and clinical candidates that target kinases. This data is obtained from the PKIDB ( 1 , 29 ), a resource dedicated to providing an up-to-date and manually curated overview of approved kinase inhibitors and clinical candidates. The list of compounds acquired from the PKIDB is screened for available data within ChEMBL using the readily provided ChEMBL IDs and the available bioactivity information is linked to each compound in KLIFS.…”

Diarylureas as Antitumor Agents

“…In particular, 8b arrested cell cycle at the S phase and induced H4IIE cells apoptosis. A library of diarylureas has been designed and the in vitro antiproliferative activities was studied against HT- 29 [111]. A series of diarylureas bearing a substituted thiadiazole as one of the two aryl moieties was studied against human chronic myeloid leukemia (CML) cell line K562.…”

“…Tivozanib is a diarylurea which is to be considered as third and fourth line therapy in patients with metastatic RCC in phase 3 study [28]. By end of 2019, the Chinese and European regulatory authorities have marketed five small-molecule protein kinase inhibitors (PKIs), including tivozanib [29]. Ripretinib has been suggested as a promising treatment for advanced GISTs [30].…”