Therapeutic Perspectives on ROCK Inhibition for Cerebral Cavernous Malformations

Abstract

Cerebral cavernous malformations (CCM) are developmental venous dysplasias which present as abnormally dilated blood vessels occurring mainly in the brain. Alterations in vascular biology originate from somatic mutations in genes regulating angiogenesis and endothelial-to-mesenchymal transition. Vascular lesions may occur at any time and develop silently, remaining asymptomatic for years. However, symptomatic disease is often debilitating, and patients are prone to develop drug-resistant epilepsy and hemorrhages. There is no cure, and surgical treatment is recommended only for superficial lesions on cortical areas. The study of lesion biology led to the identification of different pathways related to disease onset and progression, of which RhoA/Rho-associated protein kinase (ROCK) shows activation in different subsets of patients. This work will explore the current knowledge about the involvement of ROCK in the many aspects of CCM disease, including isoform-specific actions, and delineate the recent development of ROCK inhibitors for CNS-targeted diseases.

The Magic Methyl and Its Tricks in Drug Discovery and Development

“…ROCK inhibitors have emerged as interesting candidates for treating neurodegenerative diseases [ 55 , 56 ]. A series of N -sulfonylhydrazone derivatives were designed as Rho-associated kinase (ROCK) inhibitors [ 57 ] through molecular hybridization between the approved drug fasudil ( 67 ), a ROCK inhibitor [ 58 ], and 66 , a previously reported inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) [ 59 ] ( Figure 18 ).…”

“…Barbosa and colleagues [46] described a series of combretastatin A-4 analogs based on the N-acylhydrazone (NAH) LASSBio-1586 (54) with cytotoxic and antimitotic activity (Figure 14). Homologation [9] studies on the amide nitrogen led to the benzyl homolog of LASSBio-1586 (54), LASSBio-2070 (56), which showed microtubule-stabilizing behavior, while the methylated homolog, LASSBio-1735 (55), had microtubule-destabilizing behavior. In addition, none of the compounds had better cytotoxic activity when compared to the N-methylated compound LASSBio-1735 (55) [46].…”