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Novel Selective and Potent EGFR Inhibitor That Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

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Novel Selective and Potent EGFR Inhibitor That Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer molecules Article Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer Yanxia Li 1,2, Zhendong Song 3, Yue Jin 3, Zeyao Tang 3, Jian Kang 1,* and Xiaodong Ma 3,* 1 Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China; [email protected] 2 Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China 3 College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China; [email protected] (Z.S.); [email protected] (Y.J.); [email protected] (Z.T.) * Correspondence: [email protected] (J.K.); [email protected] (X.M.); Tel./Fax: +86-24-8328-3195 (J.K.); +86-411-8611-0419 (X.M.) Academic Editor: James W. Leahy Received: 30 September 2016; Accepted: 29 October 2016; Published: 2 November 2016 Abstract: Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide T790M (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFR ) (IC50 = 0.71 nM) over wild-type EGFR (IC50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFRT790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC50 value of 0.037 µM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFRT790M-mutated NSCLC. Keywords: NSCLC; EGFR T790M; resistance; pyrimidine; inhibitor 1. Introduction Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers [1]. Genetic aberrations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have been identified as key drivers of NSCLC progression [2]. Inhibition of the EGFR kinase domain and resulting oncogenic cell signaling disruption via small molecule inhibitors, such as gefitinib (1) and erlotinib (2) (Figure1) has been shown to be particularly beneficial for patients carrying the so-called “sensitizing mutations”, such as L858R or the exon-19 deletion [3–5]. Although such EGFR inhibitor drugs exhibit high response rates, clinical experiments demonstrated that approximately 60% of patients would eventually suffer from drug resistance after a treatment period, due to a conversion of the “gatekeeper” threonine 790 to methionine (T790M) [6–8]. Molecules 2016, 21, 1462; doi:10.3390/molecules21111462 www.mdpi.com/journal/molecules Molecules 2016, 21, 1462 2 of 14 Recently, irreversible EGFR inhibitors have been developed that contain a Michael acceptor functional group and that circumvent the T790M mutation-related resistance. These inhibitors form a covalentMolecules bond 2016, 21 with, 1462 Cys797 within the EGFR active site and have revealed preclinical2 of 13 activity againstMolecules T790M-containing 2016, 21, 1462 mutants of EGFR [9]. However, wild-type EGFR and EGFR2 of 13 T790M mutanta covalent share highly bond similarwith Cys797 three-dimensional within the EGFR structures active site andand virtuallyhave reveal identicaled preclinical binding activity affinities with ATP.againsta covalent Consequently, T790M-containing bond with almostCys797 mutants allwithin of EGFR thethe reported,EGFR [9]. Ho actiwever,ve irreversible site wild-type and have EGFR reveal and inhibitorsed EGFR preclinical T790M displayed activity mutant equal potenciesshareagainstagainst highly T790M-containing similar T790M three-dimensional mutant mutants and of EGFR wild-typestructures [9]. Ho andwever, enzyme, virtually wild-type highlightingidentical EGFR binding and theEGFR affinities current T790M with mutant challenge ATP. in Consequently,share highly similar almost three-dimensional all of the reported, structures irreversible and virtually EGFR inhibitorsidentical binding displayed affinities equal with potencies ATP. the search for EGFRT790M mutant-selective inhibitors [10,11]. WZ4002 (3)[12], rociletinib (4)[13], againstConsequently, T790M mutantalmost alland of wild-type the reported, enzyme, irreversible highlighting EGFR the inhibitors current displayedchallenge inequal the searchpotencies for and osimertinibEGFRagainstT790M T790M mutant-selective (5 )[mutant14,15 and] are inhibitors wild-type typical [10,11]. enzyme, EGFR WZ4002 highlighting T790M (3) inhibitors[12], the rociletinib current and challenge(4) a[13], phase and in osimertinibthe trial search has for revealed(5) capability[14,15]EGFR inT790M are gefitinib-resistant typicalmutant-selective EGFR T790M inhibitors inhibitors NSCLC [10,11]. and patients aWZ4002 phase who trial (3) [12],has suffer revealed rociletinib from capability (4 EGFR) [13], inand mutations gefitinib-resistant osimertinib (Figure (5) 1). Unfortunately,NSCLC[14,15] are patients typical only who osimertinibEGFR suffer T790M from inhibitors possessesEGFR mutations and exceptional a phase (Fig uretrial 1). has biological Unfortunately, revealed capability properties, only osimertinib in gefitinib-resistant and haspossesses thus been approvedexceptionalNSCLC in patients 2015 biological for who the sufferproperties, treatment from EGFRand ofhas mutations patients thus been (Fig withapprovedure 1). metastatic Unfortunately, in 2015 for EGFR the only treatment T790M osimertinib of mutation-positive patients possesses with NSCLCmetastaticexceptional [16]. OnEGFR biological the T790M basis properties, ofmutation-positive considerable and has thus NSCLCeffortsbeen approved to[16]. identify On in 2015the morebasisfor the of effectivetreatment considerable of and patients safeefforts with agents to to overcomeidentifymetastatic gefitinib-produced more EGFR effective T790M and mutation-positive resistancessafe agents to [17 overco– 19NSCLC],me we gefitinib-produced found[16]. On the the novel basis resistances diphenylpyrimidine of considerable [17–19], effortswe found derivative to theidentify novel more diphenylpyrimidine effective and safe derivative agents to Noverco-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-me gefitinib-produced resistances [17–19], we found N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide 4-pyrimidinyl)amino)phenyl)acrylamidethe novel diphenylpyrimidine derivative ( 6N, -(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-DY3002, Figure 2) [20]. The molecule displayed enhanced (6, DY3002,activity4-pyrimidinyl)amino)phenyl)acrylamide Figure and increased2)[ 20]. Theselectivity molecule against displayed ( 6EGFR, DY3002,T790M enhanced Figureand was 2) [20]. activitythus The reported molecule and increased as adisplayed promising selectivity enhanced NSCLC against T790M EGFRclinicalactivityand candidate. and was increased thus reported selectivity as against a promising EGFRT790M NSCLC and was clinical thus reported candidate. as a promising NSCLC clinical candidate. F F O HN Cl HN O N O HN Cl O HN N O N N O O N O N O N O N O O 1 N O 2N Gefitinib 1 Erlotinib2 Gefitinib O Erlotinib O N N N N N N O O O N N N O O O N HN N HN N HN HN HN HN O O O N O O N NH O O N NH HN N NH N O N NH HN N NH N NH N N N F C Cl N 3 N N Cl F3C 3 4 5 WZ4002 Rociletinib4 Osimertinib 3 5 WZ4002 Rociletinib Osimertinib Figure 1. Structures of novel EGFR inhibitors. FigureFigure 1. 1.Structures Structures ofof nove novell EGFR EGFR inhibitors. inhibitors. A B A Cl B Met790 N Cl N Met790 HN N N NH Asn842 HN N HN NH Asn842 H O Leu792 O Leu792 Pro794 Gly719 N Pro794 Gly719 N Leu799 O 6 Leu799 O 6 Phe795 Cys797 DY3002 Phe795 Cys797 DY3002 Lys716 IC (EGFRT790M/L858R) = 0.71 nM 50 T790M/L858R Lys716 Asp800 ICIC50(EGFR(EGFRWT) = 448.7) = nM 0.71 nM 50 WT H O Asp800 IC (EGFRT790M/L858R) = 448.7 nMWT 2 SI (EGFR50 /EGFR )= 632.0 H2O SI (EGFRT790M/L858R/EGFRWT)= 632.0 IC50(H1975 cell) = 0.037 μM IC (H1975 cell) = 0.037 μM 50 Figure 2. Structure of DY3002 (A) and its putative binding mode with EGFRT790M enzyme (B). Figure 2. Structure of DY3002 (A) and its putative binding mode with EGFRT790M enzyme (B). Figure 2. Structure of DY3002 (A) and its putative binding mode with EGFRT790M enzyme (B). Molecules 2016, 21, 1462 3 of 14 2. Results and Discussion 2.1. Inhibition of Kinase and Cancer Cell Viability As shown in Table1, DY3002 strongly inhibited EGFR T790M/L858R enzyme activity at a surprisingly low concentration of 0.71 nM. In contrast, high concentrations (460.2 nM) are necessary to interfere with wild-type EGFR. Thus, DY3002 possesses a 632.0-fold higher selectivity against EGFRT790M/L858R mutants that against wild-type EGFR, suggesting that it will reduce side effects, such as the hyperglycemia problem. Compared to rociletinib (SI = 21.4) and osimertinib (SI
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