Drugging the Undruggable: How Isoquinolines and PKA Initiated the Era of Designed Protein Kinase Inhibitor Therapeutics

Abstract

In 1984, Japanese researchers led by the biochemist Hiroyoshi Hidaka described the first synthetic protein kinase inhibitors based on an isoquinoline sulfonamide structure (Hidaka et al. Biochemistry, 1984 Oct 9; 23(21): 5036–41. doi: 10.1021/bi00316a032). These led to the first protein kinase inhibitor approved for medical use (fasudil), an inhibitor of the AGC subfamily Rho kinase. With potencies strong enough to compete against endogenous ATP, the isoquinoline compounds established the druggability of the ATP binding site. Crystal structures of their protein kinase complexes, including with cAMP-dependent protein kinase (PKA), showed interactions that, on the one hand, could mimic ATP but, on the other hand, could be optimized for high potency binding, kinase selectivity, and diversification away from adenosine. They also showed the flexibility of the glycine-rich loop, and PKA became a major prototype for crystallographic and nuclear magnetic resonance (NMR) studies of protein kinase mechanism and dynamic activity control. Since fasudil, more than 70 kinase inhibitors have been approved for clinical use, involving efforts that progressively have introduced new paradigms of data-driven drug discovery. Publicly available data alone comprise over 5000 protein kinase crystal structures and hundreds of thousands of binding data. Now, new methods, including artificial intelligence techniques and expansion of protein kinase targeting approaches, together with the expiration of patent protection for optimized inhibitor scaffolds, promise even greater advances in drug discovery. Looking back to the time of the first isoquinoline hinge binders brings the current state-of-the-art into stark contrast. Appropriately for this Perspective article, many of the milestone papers during this time were published in Biochemistry (now ACS Biochemistry).

Signaling pathways and targeted therapy for myocardial infarction

“…Injecting the above two drugs into the border area of MI significantly reduced the occurrence of fibrosis by inhibiting the RhoA/ROCK signaling pathway 306,307 . Recently, fasudil, a protein kinase inhibitor based on the structure of isoquinoline sulfonamide, was approved for clinical use as the first ROCK inhibitor 308 . Although fasudil is mainly used to treat cerebrovascular diseases 309,310 , its therapeutic effect has been demonstrated in animal models with myocardial fibrosis after MI 311,312 .…”

Targeted Molecular Profiling of Non-small Cell Lung Cancer in India

“…BRAF's kinase domain is encoded by amino acids 457 -717 (88). The activation loop of the kinase interacts with the phosphate-binding loop, locking it (89). If the activation loop is phosphorylated, BRAF can phosphorylate and activate the MAPK ERK1/2 signaling route (also known as MEK1/2).…”