Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors

Kalogirou, Andreas S.; East, Michael P.; Laitinen, Tuomo; Torrice, Chad; Maffuid, Kaitlyn; Drewry, David H.; Koutentis, P. A.; Johnson, Gary L.; Crona, Daniel J.; Asquith, Christopher R. M.

doi:10.3390/molecules26195911

Cited by 4 publications

(3 citation statements)

References 70 publications

(84 reference statements)

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“…The para-fluoro 36 was a threefold improvement in U-CH1 inhibition with EGFR activity maintained. Interestingly, switching to a para-chloro 37 reduced activity on U-CH1 by 11-fold, however, demonstrated relatively high activity on the difficult to treat U-CH2 cell line 9,10,12 , with an IC 50 = 5.0 μM compared with no activity from the rest of the mini-series (9,(34)(35)(36).…”

Section: Resultsmentioning

confidence: 99%

“…This was the case despite both 6-iodo 9 and 7-methoxy 11 displaying very potent in-cell activity against EGFR (IC 50 = 0.83 μM and 0.53 μM, respectively). However, in later optimized derivatives (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), more correspondence between EGFR and cell line inhibition was observed (Tables 5, 6). There were still exceptions, including 44 and lead compound 45, both showing potent EGFR inhibition (IC 50 = < 100 nM) but no activity against U-CH1 (IC 50 = > 100 μM), again highlighting the complexity of chordoma biology.…”

Section: Discussionmentioning

confidence: 99%

“…Cell culture method. Chordoma cell lines were cultured as described previously 10,12,33,34 . Briefly, U-CH1 and U-CH2 cell lines were cultured in 4:1 IMDM:RPMI medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin in gel-coated flasks.…”

Section: Experimental Methodsmentioning

confidence: 99%

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Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

Bieberich¹,

Laitinen

Maffuid

et al. 2022

Sci Rep

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The 4-anilinoquin(az)oline is a well-known kinase inhibitor scaffold incorporated in clinical inhibitors including gefitinib, erlotinib, afatinib, and lapatinib, all of which have previously demonstrated activity against chordoma cell lines in vitro. We screened a focused array of compounds based on the 4-anilinoquin(az)oline scaffold against both U-CH1 and the epidermal growth factor receptor (EGFR) inhibitor resistant U-CH2. To prioritize the hit compounds for further development, we screened the compound set in a multiparameter cell health toxicity assay. The de-risked compounds were then screened against a wider panel of patient derived cell lines and demonstrated low micromolar efficacy in cells. We also investigated the properties that gave rise to the toxophore markers, including the structural and electronic features, while optimizing for EGFR in-cell target engagement. These de-risked leads present a potential new therapeutic avenue for treatment of chordomas and new chemical tools and probe compound 45 (UNC-CA359) to interrogate EGFR mediated disease phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

Bieberich¹,

Laitinen

Maffuid

et al. 2022

Sci Rep

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Oxidations of 4H‐1,2,6‐Thiadiazines

2022

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The oxidation of various non-S-oxidized 4H-1,2,6-thiadiazines with N 2 O 4 , meta-chloroperbenzoic acid (m-CPBA), Oxone, [bis(trifluoroacetoxy)iodo]benzene (PIFA) and phenyliodine (III) diacetate (PIDA) is reported. Six 3,5-diamino-4H-1,2,6-thiadiazin-4-ones were oxidized to the corresponding sulfones (67-95 % yields) most efficiently using PIFA (3 equiv.). A 3,5diphenylthio analogue, however, oxidized at the exocyclic sulfur to give the asymmetric mono sulfoxide using PIFA (3 equiv.) in 86 % yield. 4H-1,2,6-Thiadiazine 4-ylidenemalononitriles, 4-ylidinemalonates and 4-phenylimines were oxidized stepwise, initially to sulfoxides using all the above reagents in 31-97 % yields and then to sulfones using N 2 O 4 , m-CPBA or Oxone in 31-89 % yields. Oxidation of a 4-thione derivative using Oxone (1.5 equiv.) gave the sulfine in 56 %. Unexpectedly, oxidation of 3,5-diphenyl-4-(phenylimino)-4H-1,2,6-thiadiazine 1-oxide with excess m-CPBA gave a fused oxaziridine in 98 % yield, while 3,5-dimorpholino-4H-1,2,6-thiadiazin-4-one 1,1-dioxide in EtOH/MeCN gave a hemiacetal in 56 % yield. Single crystal structures of 3,5-bis(phenylamino)-4H-1,2,6-thiadiazin-4one 1,1-dioxide, 4-ethoxy-4-hydroxy-3,5-dimorph-olino-4H-1,2,6-thiadiazine 1,1-dioxide, 2-(1-oxido-3,5-diphenyl-4H-1,2,6thiadiazin-4-ylidene)malononitrile, 2-[1,1-dioxido-3,5-di(thien-2yl)-4H-1,2,6-thiadiazin-4-ylidene]malono-nitrile and (E)-4,6-diphenyl-5-(phenylimino)-7-oxa-2-thia-1,3-diazabicyclo[4.1.0]hept-3-ene 2,2-dioxide are reported.

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3-(1,3-Benzothiazol-2-ylsulfanyl)-1,2,6-thiadiazinones: Surrogates for 3-halo-1,2,6-thiadiazinones

Kalogirou

Koutentis²

2022

Chem Heterocycl Comp

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Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors

Cited by 4 publications

References 70 publications

Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

Oxidations of 4H‐1,2,6‐Thiadiazines

3-(1,3-Benzothiazol-2-ylsulfanyl)-1,2,6-thiadiazinones: Surrogates for 3-halo-1,2,6-thiadiazinones

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