Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization

Abstract

Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human β-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS 167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human β-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human β-cell replication-promoting compounds yet *

Enigmatic MELK: The controversy surrounding its complex role in cancer

“…These kinases (CSNK2A2, RIPK2, CSNK2A1/3, GAK, STK10, DYRK1A, LATS1, and TAOK3) should thus be considered bona fide high-affinity targets of OTS. Finally, another study profiled the selectivity of this compound using an in vitro platform (DiscoverX), revealing that 100 nM OTS inhibited 189 of 403 kinases Ͼ65%, and 69 of 403 kinases Ͼ99% (48).…”

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

“…Moreover, in a recent study, the same reaction was applied for the synthesis of 1,5-naphthyridine 10b ( Scheme 3 ). However, in this particular case chlorobenzene was the solvent of choice to carry out the cyclization [ 21 ].…”

“…Other halogenation reactions were carried out in the preparation of fluorine intermediates (compounds 74 and 75 , Figure 2 ) [ 26 ]. In this sense, the reaction was applied for the synthesis of 1,5-naphthyridine-based polymers, new functional materials for electronics (compound 76 , Figure 2 ) [ 40 ], active naphthyridine derivatives for the development of novel anti-Ebola virus pharmacophore (compound 77 , Figure 2 ) [ 27 ], a series of naphthyridine derivatives as bromo domain inibitors (compound 72a , Figure 2 ) [ 24 ], for the development of some novel 1,5-naphthyridines as c-Met kinase inhibitors (compound 78 , Figure 2 ) [ 9 ], for the synthesis of a 1,5-naphthyridine analogues of a first in class Rpn 11-selective proteasome inhibitor (compound 79 , Figure 2 ) [ 34 ] or for the synthesis of 1,5-naphthyridine-based DYRK1A inhibitors (compound 80 , Figure 2 ) [ 21 ].…”

“…A one step synthesis of 1,5-naphthyridine-based DYRK1A inhibitors consisted in the S N Ar reaction of the 1,5-naphthyridine core by means of a variety of elaborated amines for introducing amino substituents at the four-position ( 90 , Figure 3 ) [ 21 ]. Likewise, a series of 2,8-disubstituted-1,5-naphthyridine analogues were synthesized and evaluated for in vitro antiplasmodial activity, as inhibitors of Plasmodium protein kinases (PKs).…”

“…Easily available starting materials, moderate reaction conditions, short reaction time, and higher yields of the products were the major advantages of this method [ 93 ]. A Suzuki coupling by using CsCO 3 as base and Pd(dppf)Cl 2 as catalyst was also completed for the preparation of 2-substituted 1,5-naphthyridines 142 ( Scheme 61 ) [ 21 ].…”