The discovery of RIP1 kinase inhibitor GSK2982772 in innovative drug discovery

GSK2982772 is capable of specifically binding to RIP1 and efficiently blocks TNF-dependent cellular pathways. As a new anti-inflammatory compound, it can reduce the spontaneous production of cytokines in ulcerative colitis tissue. Due to its good physicochemical properties and ADMET, it is expected to become a low-dose oral drug.

The compound is currently undergoing Phase II clinical studies with indications for plaque psoriasis, rheumatoid arthritis, and ulcerative colitis. In addition, Phase I clinical studies of inflammatory bowel disease have been completed.

Progress in research and development of GSK2982772

A good drug will eventually stand in the middle of the world stage. The success of GSK2982772 is destined to be extraordinary. How it was found will inspire and guide a group of pharmaceutical professionals in their efforts of hit identification, maybe by using a library of DNA-coding compounds to screen a target.

At first, Harris et al. did not select DNA-coding compound library screening technology when searching for RIP1 inhibitors, but screened the GSK kinase inhibitor compound library. A series of lead compounds screened are inhibitors of the type II RIP1 target capable of binding to the DFG-out conformation. However, the molecular weight of this series of compounds is too large, and weak hydrophilicity and the often off-target properties become an obstacle for further lead optimization.

They then used high-throughput screening methods to screen the GSK compound library and found the compound GSK96. This compound has good data in vitro, small molecular weight, high efficiency and selectivity. However, poor oral administration in rodents limits its further development. 

After the first two methods, they tried DNA coding compound library screening technology through ternary composite blocks (BB1, BB2 and BB3, BB refers to Building Block) and the combination of split-and-pool chemical strategy, yielding a vast library of 7.7 billion compounds.

By screening this compound library, a series of benzoxazepinone compounds that inhibit RIP1, such as GSK481, were finally discovered. The discovery process of this compound was published on JMC in February 2016. This series of compounds has significant advantages over the published RIP1 inhibitors. It is not only highly active, but also effective against RIP1 kinase in 456 kinases, showing excellent selectivity, in addition to the good oral effect in rodent test. Therefore GSK481 is a very good starting point for the optimization of preclinical candidate compounds.

After optimizing GSK481, Harris et al. obtained the compound GSK2982772, and the properties of the optimized compound were greatly improved. It has good activity data, single kinase target selectivity, excellent preclinical PK data and extensibility, so it could be regarded as first-in-class in the field of RIP1 inhibitors and entered clinical trials in 2015. Now, it have completed a Phase I clinical study of indications, and three other indications are in Phase II clinical research.

Although GSK481 and GSK2982772 are similar in chemical structure, they have done a lot of work both in the discovery process and in the optimization process. It is worth noting that at the end of 2016, the editorial department of J. Med. Chem. selected six articles from 2015 to 2016, one of which was the article on GSK481 using DNA coding compound library screening technology.

Although the DNA coding compound library technology has been used as a new drug development tool by many companies, many of them are pharmaceutical giants, but there have always been doubts about the feasibility of DNA coding compound libraries. What Harris et al. has discovered is a strong proof for it.