Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration

Abstract

The pyrimidine core has been utilized extensively to construct kinase inhibitors, including eight FDA-approved drugs. Because the pyrimidine hinge-binding motif is accommodated by many human kinases, kinome-wide selectivity of resultant molecules can be poor. This liability was seen as an advantage since it is well tolerated by many understudied kinases. We hypothesized that nonexemplified aminopyrimidines bearing side chains from well-annotated pyrimidine-based inhibitors with off-target activity on understudied kinases would provide us with useful inhibitors of these lesser studied kinases. Our strategy paired mixing and matching the side chains from the 2- and 4-positions of the parent compounds with modifications at the 5-position of the pyrimidine core, which is situated near the gatekeeper residue of the binding pocket. Utilizing this approach, we imparted improved kinome-wide selectivity to most members of the resultant library. Importantly, we also identified potent biochemical and cell-active lead compounds for understudied kinases like DRAK1, BMP2K, and MARK3/4.

Modulation of Tau Tubulin Kinases (TTBK1 and TTBK2) Impacts Ciliogenesis

“…In addition to TTBK1 and TTBK2, PAK3–6, TAOK1–3, TSSK1–4, and MARK3–4 were included based on potent inhibition of one or more kinase(s) in the family by AMG28 when profiled at 1 μM (Figure 1B). Furthermore, PAK, MARK, and TAOK family kinases are of interest since they have implications in neurodegenerative disease signaling (Drewry et al, 2022a). The addition of HIPK1 and MAP4K5 completed our panel.…”

“…Analysis of kinetic solubility was carried out by Analiza, Inc using 10 mM DMSO stocks of compounds in phosphate buffered saline solution (PBS) at pH 7.4 as described previously (Drewry et al ., 2022a). Calculated solubility values in Table 2 have been corrected for background nitrogen present in the DMSO and media.…”

AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery

“…Analyses were executed using 10 mM DMSO stocks of AD Informer Set compounds in aqueous buffer at neutral pH (7.4) by Analiza, Inc via total chemiluminescent nitrogen determination as previously described. 32 Because this method relies on nitrogen detection for quantification, no kinetic solubility value could be determined for compounds lacking nitrogen in their structure (16 in total). All calculated solubility values, after correction, are included in the supporting information annotation file.…”

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

“…The active MARK4 inhibitors, described with submicromolar to have a low-nanomolar range of action, contain the indispensable central core of the pyrimidine, which appears to be a required pharmacophore feature in interactions with this kinase, while a variety of the remaining substitutions enhances the inhibitory power [ 69 , 70 , 71 , 72 , 73 , 74 ]. The most active pyrimidine MARK4 inhibitors 22 – 28 (IC 50 < 100 nM) are shown in Figure 7 [ 69 , 70 , 71 , 72 , 73 ].…”

“…The supporting information can be downloaded at: . References [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 143 ] are cited in the supplementary materials.…”