Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Abstract

Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors.

Development and Clinical Applications of PI3K/AKT/mTOR Pathway Inhibitors as a Therapeutic Option for Leukemias

“…Idelalisib, also known as CAL-101 or GS-1101, is a selective inhibitor of the PI3Kδ isoform. It was approved by the Food and Drug Administration (FDA) in June 2014 for the treatment of patients with CLL, follicular non-Hodgkin lymphoma (LF) of relapsed B-cell and relapsed small lymphocytic lymphoma (SLL) (45,84,85).…”

“…Hydrogen bonds, mediated by water molecules, are also formed between purines N7, N1 and the side chain of Asp-911. In addition, this drug is also capable of making hydrophobic bonds with other protein residues, such as RS4, CS6, CS7, Val-827, Met-900, among others (Figure 2) (45,84,(86)(87)(88).…”

Stereoselective Construction of 3-(Aminoalkylidene)oxindoles in One Pot: Development of a Novel, Robust, and Scalable Process for the Multigram-Scale Preparation of Nintedanib

“…Oxindole is often found in bioactive molecules or drug candidates as a privileged motif, which has driven significant attention toward finding novel methods for their synthesis . It has also been widely utilized to develop antagonists for a range of enzymes .…”

Indolin-2-one based scaffold for the development of multi- kinase inhibitor: Focus on sunitinib as an anticancer agent

“…Numerous publications have described 3-substituted indolin-2-ones or oxindole act as strong and specific inhibitors of various kinases [5]. Since sunitinib is the first small molecule with the oxindole template against various kinases, pyrroleindoline-2-ones have been extensively studied for the inhibition of VEGFR, PDGFR, the stem cell factor receptor (KIT), the Fms-like tyrosine kinase-3 receptor (FLT3), and Colony-stimulating factor-1(CSF-1R) [6].…”