Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity

Abstract

Herein we report the discovery of compound 6 [KST016366; 4-((2-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)benzo[d]thiazol-6-yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A. In vitro anticancer evaluation of 6 showed substantial broad-spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI50 values of 51.4 and 19 nm against leukemia K-562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar-level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC50 values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL-1 (wild-type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

“…This resulted in a remarkable increase in the cellular antiproliferative potency as well as favorable inhibitory activity toward B-Raf (V600E) and C-Raf kinases. However, the physiochemical properties needed further improvement, which was carried out through replacing the small lipophilic chlorine atom with either (morpholin-1-yl)methyl ( 37 , Figure 14 ) or (4-ethylpiperazin-1-yl)methyl moieties ( 38 , Figure 14 ) [ 146 ]. These two compounds were evaluated for their antitumor effects over a panel of 60 human cancer cell lines where they exhibited promising antiproliferative effects over numerous cell lines such as HL-60 (leukemia), HOP-92 (non-small cell lung cancer), HCT-116 (colon cancer), SF-5339 (CNS cancer) and SK-MEL-28 (melanoma).…”

KinomeRun: An interactive utility for kinome target screening and interaction fingerprint analysis towards holistic visualization on kinome tree

“…Further, reanalysis was performed by specifying the explicit presence of halogen: 79 th position interactions in the All_pose_structure file and the resultant targets were mapped on to the kinome tree Figure 5a. The known wild targets of sorafenib: ABL1 (Kurosu, Ohki, Wu, Kagechika, & Miura, 2009), p38a (Namboodiri et al., 2010), CDK8 (Schneider et al., 2011), MET (Beizaei et al., 2019), TRKB (Kumar et al., 2009), FLT3, FLT1 (Wilhelm et al., 2004), RIPK1 (Martens et al., 2017), DDR1 (El‐Damasy, Cho, Nam, Pae, & Keum, 2016; Kitagawa et al., 2013) and the mutant targets such as JNK2 (functional disability due to this mutation is not reported, hence was considered as wild type; Broecker‐Preuss et al., 2015), BRAF V600E (Wan et al., 2004), KDR T940V (Okamoto et al., 2015), KIT mutant and KIT WT (Wilhelm et al., 2004) were also identified as top‐ranking hits as per the maximal number of interaction patterns, and EphB4 Y774E_A803V_V870I (functional disability due to this mutation is not reported, hence was considered as wild type; Wang et al., 2017), PEK D937N (but wild PEK inhibition is reported [Shiota et al., 2010]), FMS C667T_C830S_C907T (functional disability due to this mutation is not reported, hence was considered as wild type; Uitdehaag et al., 2011; Ullrich et al., 2011) were identified to be mapped on the kinome tree Figure 5a & Table S5. The other targets of sorafenib: CDK2 (WT) and MELK mutant were also found during target prioritization.…”

Recent Advances and Developments of in vitro Evaluation of Heterocyclic Moieties on Cancer Cell Lines

“…El‐Damsay et al . have also reported new benzothiazole derivatives with remarkable anticancer activity by replacing the phenoxy linker in sorafenib with benzothiazole and replacing the chloro derivative with morpholine or N ‐methyl piperazine moiety (Figure ).…”