Identification of TRD‐35 as Potent and Selective DRAK2 Inhibitor

Abstract

Proposed binding mode of TRD‐35 (thick cyan sticks) in the DRAK2.

A New Method for the Synthesis of 3-Thiocyanatopyrazolo[1,5-a]pyrimidines

“…MeCN (99.9%, for HPLC), EtOH (95%, for analysis), water (for analysis), toluene (99+%, extra pure), EtOAc (99+%, extra pure), NH 4 SCN ( 2 ) (99+%, extra pure), KSCN (98%, pure), NaSCN (98%, extra pure), NaClO 4 (98%, extra pure), Na 2 SO 4 (99%, extra pure, anhydrous), HCl (32% solution in water, for analysis,), H 2 SO 4 (96% solution in water, for analysis,), AcOH (99.6%, for analysis), 1,1,3,3-tetraethoxypropane (97%) ( 4a ), 2,4-pentanedione (99+%) ( 4b ), 1,1,1-trifluoro-2,4-pentanedione (98%) ( 4e ), 4,4,4-trifluoro-1-phenyl-1,3-butanedione (99%) ( 4g ), 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (99%) ( 4h ) (Acros Organics, Geel, Belgium) were used as purchased. 3-Methyl-1 H -pyrazol-5-amine ( 1a ), 3-cyclopropyl-1 H -pyrazol-5-amine ( 1b ), 1,1,1-trichloro-4-ethoxybut-3-en-2-one ( 4c ), 4-ethoxy-1,1,1-trifluorobut-3-en-2-one ( 4d ), 1-cyclopropyl-4,4,4-trifluorobutane-1,3-dione ( 4f ) were prepared using reported [ 35 , 36 , 37 , 38 ] procedures. More spectral data can be found at Supplementary Materials section.…”

A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation

“…The residual chloroform signal, CHCl3 (δ = 7.26) was used as reference and for DMSO signal (quintet, centerline δ = 2.50) was used as reference. 13 C NMR chemical shifts are reported as δ values in parts per million (ppm) relative to TMS and DMSO signal (septet, centerline δ = 39.52) as reference. Analytical thin layer chromatography (TLC) was performed on silica gel plates, 200 μm with F254 indicator, visualization was accomplished by UV light (254/365 nm) or 3% ethanol solution of phosphomolybdic acid.…”

“…11p, 11s, 11h and 11o bearing p-morpholino, benzothiophene, p-cyclopropyl, and m-morpholino group, respectively, showed even greater metabolic stability, each with >50% of the compound remaining after 30 min (Table 7, entries 9-12). The fluorinated analogs 11z, 11aa, and 11x showed the best metabolic stability in the series ( Table 7, entries [13][14][15]. None of the analogs showed improved aqueous solubility over 4 despite changes in their calculated LogD.…”

“…HRMS (HESI) calcd for C16H13N3O3S2 [M+H] + 360.0476, found 360.0463. .68 (ddd, J = 11.1, 7.9, 1.9 Hz, 2H), 7.48 (t, J = 7.9 Hz, 1H), 4.27 (s, 2H), 3.32 (s, 3H); 13 C NMR (176 MHz, DMSO) δ 169. 4,168.7,161.2,159.3,154.1,151.6,140.2,132.2,130.0,126.7,121.4,120.6,120.1,116.7,31.5,24.1.…”

“…Several other inhibitors have shown up to 20-fold selectivity for STK17B within the DAPK family, but none of them have been reported to be cell active. [11][12][13] Benzofuranone 3 is the only inhibitor with modest STK17B selectivity that was also reported to be active in cells. In a phenotypic assay, 3 protected islet bcells from apoptosis induced by free fatty acid palmitate.…”