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Computationally guided design of N4-(2-methyl-2H-indazol-6-yl)-N2-phenylpyrimidine-2,4-diamine inhibitors of EGFR kinase targeting Cys797
(2026-03-01)
Konsue, Adchata
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Gleeson, Duangkamol
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Choowongkomon, Kiattawee
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Jones, Donald J.L.
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Hannanta-anan, Pimkhuan
The epidermal growth factor receptor kinase (EGFR) is a tyrosine kinase (TK) implicated in the uncontrolled growth of non-small cell lung cancer. EGFR-TK inhibitors have been used extensively, however inhibitor resistance often develops leading to disease progression. In this work, we report the computationally guided design and preparation of novel covalent 2,4-diaminopyrimidine EGFR-TK inhibitors, inspired by Osimertinib. Molecular dynamics simulations and quantum mechanical (QM) calculations were performed on novel designs incorporating a 2-methyl-2H-indazol-6-amine at the 4-position of pyrimidine as well as various linkers and electrophiles. Calculations suggested swapping the 5-pyrimidine -H atom for -Cl would lead to a preferential “out” ligand conformation that favored T790M enzyme which was later confirmed experimentally. Compound 19 was the most potent inhibitor of WT EGFR (3.0 nM) observed, more potent than the EGFR WT inhibitor Erlotinib (5.9 nM). Compounds 48 and 49 demonstrated better activity for the double-mutant EGFR (3.0 & 2.0 nM, respectively) than Osimertinib (12.8 nM). The selectivity of these compounds for the DM was found to be comparable to Osimertinib (∼20 fold) while their phosphate buffer solubilities were > 50-fold better than both marketed drugs. Kinetic evaluation of 48 (propenamide moiety) vs 49 (acrylamide electrophile) confirms k<inf>inact</inf>/K<inf>i</inf> values consistent with a covalent mode of action for the latter, but not the former. 2009 Elsevier Ltd. All rights reserved.
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Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer
(2024-11-01)
Konsue, Adchata
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Lamtha, Thomanai
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Gleeson, Duangkamol
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Jones, Donald J.L.
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Britton, Robert G.
Epidermal growth factor receptor (EGFR) kinase has been implicated in the uncontrolled cell growth associated with non-small cell lung cancer (NSCLC). This has prompted the development of 3 generations of EGFR inhibitors over the last 2 decades due to the rapid development of drug resistance issues caused by clinical mutations, including T790M, L858R and the double mutant T790M & L858R. In this work we report the design, preparation and biological assessment of new irreversible 2,4-diaminopyrimidine-based inhibitors of EGFR kinase. Twenty new compounds have been prepared and evaluated which incorporate a range of electrophilic moieties. These include acrylamide, 2-chloroacetamide and (2E)-3-phenylprop-2-enamide, to allow reaction with residue Cys797. In addition, more polar groups have been incorporated to provide a better balance of physical properties than clinical candidate Rociletinib. Inhibitory activities against EGFR wildtype (WT) and EGFR T790M & L858R have been evaluated along with cytotoxicity against EGFR-overexpressing (A549, A431) and normal cell lines (HepG2). Selectivity against JAK3 kinase as well as physicochemical properties determination (logD<inf>7.4</inf> and phosphate buffer solubility) have been used to profile the compounds. We have identified 20, 21 and 23 as potent mutant EGFR inhibitors (≤20 nM), with comparable or better selectivity over WT EGFR, and lower activity at JAK3, than Osimertinib or Rociletinib. Compounds 21 displayed the best combination of EGFR mutant activity, JAK3 selectivity, cellular activity and physicochemical properties. Finally, kinetic studies on 21 were performed, confirming a covalent mechanism of action at EGFR.
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Design, synthesis and evaluation of N 2 ,N 4 -diaminoquinazoline based inhibitors of phosphodiesterase type 5
(2019-01-15)
Pobsuk, Nattakarn
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Paracha, Tamkeen Urooj
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Chaichamnong, Nattiya
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Salaloy, Nattapas
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Suphakun, Praphasri
We describe the design, synthesis and evaluation of a series of N 2 ,N 4 -diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC <inf>50</inf> = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC <inf>50</inf> s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
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Synthesis, plasmodium falciparum inhibitory activity, cytotoxicity and solubility of n2,n4-disubstituted quinazoline-2,4-diamines
(2019-01-01)
Pobsuk, Nattakarn
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Suphakun, Praphasri
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Hannongbua, Supa
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Nantasenamat, Chanin
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Choowongkomon, Kiattawee
Background: Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as anti-parasitic compounds over three decades ago and have remained of interest to date in industry and academia. Objective: An anti-malarial SAR evaluation of previously unreported N2,N4-disubstituted quina-zoline-2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties. Method: The synthesis of N2,N4-disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach. Results: We identified compounds 1 and 6p as sub µM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low µM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 µM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines. Conclusion: Twenty one N2,N4-Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.
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Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl-N-phenylpyrimidin-2-amines
(2017-01-01)
Toviwek, Borvornwat
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Suphakun, Praphasri
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Choowongkomon, Kiattawee
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Hannongbua, Supa
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Gleeson, M. Paul
Reported herein are efforts to profile 4-aryl-N-phenylpyrimidin-2-amines in terms of their anti-cancer activity towards non small-cell lung carcinoma (NSCLC) cells. We have synthesized new 4-aryl-N-phenylpyrimidin-2-amines and assessed them in terms of their cytotoxicity (A549, NCI-H187, MCF7, Vero & KB) and physicochemical properties (logD<inf>7.4</inf> and solubility). 13f and 13c demonstrated potent anti-cancer activity in A549 cells (0.2 µM), compared to 0.4 μM for the NSCLC drug Doxorubicin. 13f also displayed low experimental logD<inf>7.4</inf> (2.9) and the best solubility (∼40 μM). Compounds 13b and 13d showed the best balance of A549 anti-cancer activity and selectivity. 13g showed good activity and selectivity comparable with the anti-cancer drug Doxorubicin.

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