Identification and optimisation of 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors

An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives

“…The best PI3Kα inhibitory activity was recorded for compounds in which the amide group was substituted with a cis-3-methylproline amide residue and position 2 of the thiazole ring was substituted with a quaternary alkyl residue. Subsequently, based on the obtained results, a new series of 4,5-dihydrobenzo [1,2-d:3,4-d]bisthiazole tricyclic compounds (58, Figure 12) was developed, the enzyme inhibition ability of these molecules being superior to 4,5-bisthiazoles [121].…”

Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor

“…To determine the class IA PI3K activities, a set of mechanistic assays in a Rat1 rat fibroblast cell line was used to assess both potency and selectivity. The use of these assays as the primary on-target screen had been successfully validated in previous PI3K projects within Novartis, including the identification of the PI3Kα selective inhibitor alpelisib. − For each isoform, the p110 catalytic subunit is stably expressed in a constitutively activated form (myristylated), and PI3K activity is determined by the extent of Akt phosphorylation on Ser473 (S473P-Akt) using a reverse phase protein array (RPPA) readout . These Rat1-myr-p110 cell lines were additionally implanted into rodents to generate tumor xenograft models, and these mechanistic models were used to establish PK/PD/efficacy relationships as part of the optimization screening cascade .…”

Design, Synthesis and in vitro Anti-Cancer Activity of Novel Ethyl 4-Oxo-2-iminothiazolidin-5-ylidene Acetates

“…Among various anti-cancer agents, N/S-containing heterocycles attract much attention because of their versatile frameworks in medicinal chemistry. [4] In particular, thiazolidones and their derivatives exhibit broad-spectrum anti-cancer activities by acting on various targets including epidermal growth factor receptor (EGFR) kinase, [5] histone acetylase/histone deacetylase (HAT/HDAC), [6] Src/Abl kinase, [7] sphingosine kinase (SphK), [8] phosphatidylinositol 3-kinases (PI3Ks), [9] BRAF kinase [10] and tubulin protein. [11] For example, darbufelone (I) is able to inhibit the proliferation of human non-small cell lung cancer cell lines, which can be used in lung cancer chemotherapy (Figure 1).…”