Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities – Part 1

Article abstract of DOI:10.1016/j.bmcl.2018.12.056

Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors became popular after the approval of Afatinib by FDA to overcome the mutation related problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors. Selected twenty four compounds were reported here with significant inhibitory activities against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC₅₀ values. In vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour xenograft model was discussed.

Full text of DOI:10.1016/j.bmcl.2018.12.056

Accepted Manuscript
Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 in-
hibitors and their anticancer activities- Part 1
Debasis Das, Lingzhi Xie, Jingbing Wang, Xin Xu, Zonghua Zhang, Jingli Shi,
Xiaoyong Le, Jian Hong
PII:
S0960-894X(18)31002-3
https://doi.org/10.1016/j.bmcl.2018.12.056
BMCL 26225
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
9 October 2018
17 December 2018
24 December 2018
Please cite this article as: Das, D., Xie, L., Wang, J., Xu, X., Zhang, Z., Shi, J., Le, X., Hong, J., Discovery of new
quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities- Part 1, Bioorganic
&
Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.12.056
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2
inhibitors and their anticancer activities- Part 1
Debasis Das*, Lingzhi Xie, Jingbing Wang, Xin Xu, Zonghua Zhang, Jingli Shi, Xiaoyong
Le, Jian Hong*
Discovery Chemistry Research, Arromax Pharmatech Co. Ltd.
Sangtian Island Innovation Park, No. 1 Huayun Road, Suzhou 215123, P. R. China.
*
Corresponding authors:
Email: debasis.das@arromax.com (D. Das) & eric.hong@arromax.com (J. Hong).
_
________________________________________________________________________
Abstract
Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate
cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors
became popular after the approval of Afatinib by FDA to overcome the mutation related
problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were
designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors.
Selected twenty four compounds were reported here with significant inhibitory activities
against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC values. In
5
0
vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA
MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to
standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour
xenograft model was discussed.
Keywords: EGFR, HER2, dual inhibitor, quinazoline, antitumor, anticancer, irreversible,
tyrosine kinase.
The human epidermal growth factor receptor (HER) family consists of four members of
tyrosine kinase (TK) receptors: HER1 (EGFR/ErbB1), HER2 (ErbB2/neu), HER3 (ErB3) and
HER4 (Erb4). A complex signalling cascade occurs through homo- and hetero dimeric HER
complexes formation. The downstream signalling modules after HER complex formations
follow the RAS/RAF/MEK/ERK1/2, phosphatidylinositol 3-kinase and Akt (Protein kinase B)
PI3K-Akt/mTOR pathways.1,2 The downstream signalling pathways lead to cell proliferation,
adhesion, survival, differentiation and apoptosis. Several malignancies, including lung, breast,
stomach, colorectal, pancreatic, head & neck cancers and glioblastoma are associated with

overexpression or mutation of HER oncogene. Overexpression or amplification of HER2
oncogene is observed in 25–30% of breast cancer and ovarian cancer patients.3-5 HER2 gene
6
overexpression is detected in non-small cell lung cancer (NSCLC) , prostate cancer and
prognostic factor for gastric cancer.7, 8
The U.S. Food and Drug Administration (FDA) approved several EGFR and HER2
targeted therapeutics in recent years.
The selective EGFR tyrosine kinase inhibitors –
gefitinib (Iressa, ZD1839)9, 10 and erlotinib (Tarceva, OSI-774)11 were approved for non-
small-cell lung cancer (NSCLC) treatment. Lapatinib, a reversible dual EGFR/HER2 TK
inhibitor used for breast cancer, especially for the patient who showed resistance to
trastuzumab based therapy.12,13 However, the EGFR tyrosine kinase (TK) inhibitors are
limited by the up-regulation of bypass signalling pathways and acquired point mutations.14, 15
After treatment 10–16 months with these inhibitors, approximately 50% of the NSCLC
patients gained an additional gate keeper mutation (T790M) that decreases sensitivity to
gefitinib or erlotinib and increases the binding affinity for ATP. After the advancement of the
first generation drugs, many scientists conducted clinical studies to overcome various
mutations, including EGFR and KRAS mutations.16-18 A number of new-generation
irreversible inhibitors were reported to overcome EGFR mutations (L858R and T790M)
related drug resistances.19, 20
Fig. 1. Second generation irreversible EGFR/HER2-TK inhibitors.

Afatinib (Gilotrif, BIBW-2992) (Figure 1), the second generation irreversible dual
EGFR/HER2 inhibitor got approval by FDA for the treatment of late-stage NSCLC patients
2
1
with actively mutated EGFR. Erlotinib and gefitinib worked on EGFR and not worked on
EGFR and KRAS mutations. Afatinib was reported to be superior to erlotinib and gefitinib on
EGFR mutation. Being an EGFR/HER2 inhibitor, afatinib showed good results for the
2
2
treatment of lung cancer carrying both EGFR and KRAS mutations. Neratinib (HKI-272)
was used for advanced HER2 positive breast cancer.23 Dacomitinib was launched for the
treatment of NSCLC.24, 25 Identifying efficacious irreversible EGFR/HER2 dual inhibitors
remain the focus of research interest for future drugs.26
In this article, we report the synthesis and biological evaluation of new quinazoline
derivatives of general structure 1 (Figure 1). To make irreversible EGFR/HER2 dual
inhibitors, a Michael acceptor was kept at the 6-position of quinazoline ring for Michael
addition with the thiol group (–SH) of cysteine (Cys773) on the active center pocket wall of
EGFR tyrosine kinase. The SAR studies were done by changing the size of alkoxyalkane
chains at 7-position (1a-f), different substitutions on aryl units at 4-position (1g-k) and
different Michael acceptors at 6-position of the quinazoline core (1l-x). In vitro
pharmacological profile and in vivo antitumor activities of selected compounds were reported.

2
7
Many synthetic methods are known to construct the quinazoline derivatives. The new
quinazoline derivatives were made in two ways –“one pot” synthesis, starting with the
qunazoline core and step-wise synthesis via Dimroth rearrangement reaction. In “One pot”
synthesis, 7-fluoro-6-nitro-quinazolin-4-ol (2) was converted to 4-chloro-7-fluoro-6-nitro-
quinazoline (3) using phosphorous oxychloride. Intermediate 3 was allowed to react with 3-
chloro-4-fluoro-aniline (4) to afford quinazoline 5 (Scheme 1). In Dimroth rearrangement
condition, the synthesis was started from commercially available 2-amino-4-fluoro-
benzonitrile (6). Acetylation of 6 followed by nitration gave 8 in good yield. The hydrolysis
of amidegroup of 8 was done under acidic condition and the aniline 9 was reacted with N,N-
dimethylformamide dimethyl acetal (DMF-DMA) to give 10. Then 3-chloro-4-fluoro-aniline
(4) was reacted with 10 to give quinazoline 5 in moderate yield (62%).
The quinazoline derivatives 1a-f with different 7-alkoxyalkoxide chains were made in
Scheme 2. In presence of sodium hydride (NaH), alkoxy alkanols (ethylene / propelene glycol
o
o
methyl ether) were reacted with 5 at low temperature (‒15 C to –20 C) to give 7-alkoxy
quinazolines 11a-f. The 6-nitro group of 11a-f was easily reduced to give 7-alkoxy-6-amino

quinazolines 12a-f by tin(II) chloride dehydrate and hydrochloric acid or iron powder in
o
o
acetic acid conditions at 40 C to 60 C temperature for 30min to 3hrs. (E)-4-(dimethylamino)-
but-2-enoyl chloride was prepared in situ from corresponding acid and oxalyl chloride
reaction. Then (E)-4-(dimethylamino)but-2-enoyl chloride was reacted with 12a-f separately
to give quinazoline derivatives 1a-f in moderate yields (46-84%). The quinazoline derivatives
1
g-k with substituted phenyls at 4-position were prepared in Scheme 3.
The nitroquinazolines 13g-k were prepared with different aryl units from 2 and allowed to
reacted with 2-ethoxyethanol in presence of sodium hydride to give 7-(2-
ethoxyethoxy)quinazolines 14g-k in good yields. Reduction of nitro to amines 15g-k,
followed by (E)-4-(dimethylamino)but-2-enoyl chloride reaction led to compounds 1g-k in
moderate yields (42-65%). The 6-aminoquninazoline 12d was allowed to react with
substituted acryloyl chlorides or vinyl sulfonyl chlorides to give compounds 1l-x (Scheme 4).

The anti-proliferation activities of these newly synthesized twenty four compounds,
1
a-x were evaluated by cell proliferation assay kits (CCK8) (Supplementary material). In vitro
cell proliferation were studied on three lung cancer cell lines human cell lines- human non-
small cell lung cancer cell lines (NCI H1975), human non-small cell lung cancer cell line
(HCC 827), human epithelial carcinoma cell lines (A431) which were harbouring EGFR
T790M, L858R mutants, wild type EGFR (EGFRWT) respectively and human breast cancer
cell lines (MDA-MB-453). To identify efficacious irreversible EGFR/HER2 inhibitors with
more potent antitumor activities, all newly synthesized compounds were tested using afatinib
as the reference standard. The data of twenty four compounds are summarized in Table 1.

Table 1. Inhibitory activities of compounds 1a-x on different cell lines
NCI-H1975
IC50(nM)
36.09
49.92
66.50
12.20
10.63
41.73
49.66
106.80
7.30
HCC 827
IC50(nM)
0.29
A431
IC50(nM)
23.34
43.03
16.70
1.52
MDA-MB-453
IC50(nM)
N.D
Cell lines
Compounds
CLogP
5.01
4.94
4.94
5.02
5.55
5.33
6.51
5.39
4.49
4.88
3.38
4.49
4.96
5.24
4.09
5.51
6.11
6.20
5.30
5.21
5.21
6.08
5.25
5.06
4.49
1
a
1
b
0.27
N.D
1
c
0.34
N.D
1
d
0.31
0.62
1
e
0.55
8.15
N.D
1
f
0.55
5.86
N.D
1
g
2.54
79.49
64.13
20.06
13.68
6.48
N.D
1
h
2.90
2.55
1
i
3.43
1.65
1
j
6.17
0.34
2.52
1
k
65.60
18.37
51.81
13.72
49.31
72.49
37.11
39.44
8.21
0.53
12.70
0.68
1
l
5.56
94.82
6.01
1
m
0.15
5.67
1
n
3.95
3.37
130.50
3.42
1
o
p
q
1.46
11.45
54.45
368.90
572.20
296.60
289.10
24.02
5.45
1
0.53
58.20
3.71
1
33.22
6.39
1
r
15.05
3.99
1
s
4.86
1
t
7.43
7.81
14.87
N.D
1
u
1.60
7.78
1
v
190.40
27.56
35.23
96.07
1.31
N.D
1
w
0.15
148.20
207.40
10.21
18.30
21.57
N.D
1
x
0.987
0.4376
Afatinib
N.D = Not detected, CLogP calculated on Chemdraw

By changing the alkoxy group at 7-position of the quinazoline ring, we got more
potent compounds which displayed higher antiproliferative activity on H1975 cells (IC =
50
6
.1-13.7 nM). Compound 1a was better than afatinib in H1975 and HCC827. The chirality on
the alkoxy chain (1b & 1c) had no significant effect on antiproliferative inhibitory effect on
H1975 and HCC827. Whereas 1c was superior almost by three fold active than 1b for A431.
Compound 1d was better in all four cell lines. Aryl group SAR at 4-position of the
quinazoline ring was done for compounds 1g-l. It was observed that 1h & 1l was better for
H1975 and A431, 1j was better in H1975 compared to afatinib. Compounds containing
different Michael acceptors at the 6-amino position of the quinazolines (1m, n, o, v) showed
better results in H1975 and A431 cell lines.
Table 2.
In vitro inhibitory activities of the compounds against EGFR and HER2
enzymes
Compounds
IC against EGFR (nM)
IC against HER2 (nM)
5
0
50
1
a
0.76
0.94
2.73
0.69
2.84
1.54
153.50
1.48
0.96
39.26
148.30
482.10
42.11
1
b
1
c
1
d
1
e
131.60
83.84
1
f
1
1
g
v
261.80
10.94
Afatinib
73.72
In vitro kinase inhibitory activities for EGFR and HER2 enzymes were done for most
of the synthesized quinazolines. In vitro kinase analysis was performed using the HTRF
kinEASE TK kit of Invitrogen Co. The result of the compounds 1a-h and 1v were summarized
in Table 2. Compounds 1a, 1d effectively inhibited the in vitro kinase and showed better

activities of EGFR (IC = 0.76, 0.69 nM) and HER2 (IC = 39.2, 42.1 nM) respectively
5
0
50
compared to afatinib (EGFR IC = 0.96 & Her2 IC = 73.72nM). The chiral variation of the
5
0
50
alkoxy chain 1b and 1c were poor inhibitors for HER2. So, we kept the ethyleneglycol ethyl
ether chain at C-7 position of the quinazoline scaffold and changed the substituent on the N-
aryl unit. Compound 1v was weaker in EGFR activity (IC = 1.4nM) and better for Her2
5
0
activity (IC = 10.9nM) than afatinib. In enzymatic assay, the length of the side chain played
5
0
a major role in EGFR activity. The optimum chain length was observed six-atoms to show
nanomolar activity, e.g. 1a, 1d. The longer chain lengths e.g. 1e seven atoms and branched
chain 1f reduced activity 2.84 nM and 1.54 nM respectively. Chiral examples 1b & 1c
showed little poorer activity than six atom lengths. 1b was superior to 1c by three times due to
match and mismatch topology. So, six atoms linker was the optimum chain length at 7-
position of quinoline for better inhibitory activity. HER2 activities of the examples were in the
similar trend as EGFR. The inhibitory activity of compounds 1a and 1d on HER2 were better
than afatinib.
Table 3. In vivo therapeutic effect of 1d on NCI-H1975 nude mice xenografts
Group
Animal
No. (pcs)
Administra Dosage RTV
Inhibition T/C(%)
rate (%)
tion mode
(mg/kg)
d22
Blank control
8
8
qd
qd
0
7.45±1.26
1.67±0.20
---
---
Positive control
20
67.6**
22.44
(afatinib)
1
1
1
d
d
d
8
8
8
qod
qod
qd
80
20
5
0.43±0.05 95.1***
5.75
18.71
26.91
1.39±0.40
2.00±0.29
82.0**
73.2**
Notes: (1) compared with the positive control group, *p<0.05，**p<0.01，***p<0.001. ;
2) qd: administrated every day；qod：administrated every other day；(3) d22：the time of
observed 7 days after the last administration
(

Many compounds in the series showed good in vitro activities in different cell lines.
However, only few of them such as compound 1d displayed good pharmacokinetics properties
and bioavailability, and thus 1d was selected for further in vivo studies. The intravenous
dosing (5mg/Kg) and PO dosing (10mg/Kg) of 1d and its maleate salt were done on Sprague
Dawley rats. The oral bioavailability of 1d on was 46% and its malete salt was 70%. The
compound 1d showed T1/2 = 6.8h, Tmax = 4h and Cmax = 92.3g/L. So, the compound 1d
was selected for in vivo anti-tumor efficacy study.
We were interested to find active compound from this series for the mutant specific
lung cancer. The human non-small cell lung cancer cell lines NCI-H1975 mice xenograft was
2
8
suitable for T790M mutant studies. A tumor xenograft model was established by injecting
NCI-H1975 cells into nude mice of age 6-7 weeks. When tumors growth reached to 100-200
3
mm , the mices were administrated orally with 1d at lower dose 5mg/kg daily or every other
day at middle and higher doses of, 20 and 80 mg/kg, respectively. It was continuously
administrated for 14 days (d14) and observed for 7 days (d22) in Table 3. Established afatinib
(20 mg/kg) treated mice were included as positive controls. The negative control group was
administrated with the same amount of solvent (saline solution of 1% DMSO), during the
period of administration and recovery. Very good dose-dependent tumor growth inhibitions
were observed with treatment of compound 1d (Table 3). The tumor inhibition rates were
observed 95.1%, 82.0%, 73.2% for high, middle and lower doses respectively. The observed
tumor inhibition rates of 1d were better than afatinib (67.6%). Middle dose of compound 1d
every other day (20mg/kg, PO, qod) was efficacious than afatinib middle dose everyday
(20mg/kg, PO, qd). In vivo efficacy showed that the compound 1d had better tumor inhibition
effect in NCI-H1975 constructed tumors model than afatinib (Figure 2).

Fig. 2. In vivo efficacy study of 1d in mice model.
In conclusion, a series of new quinazoline derivatives of structure 1a-x were designed,
synthesized and evaluated for bioactivity in vitro and in vivo. The synthesized compounds
were tested against four human tumor cell lines (NCI-H1975, HCC 827, A431, and MDA-
MB-453). A few compounds exhibited single-digit nanomolar anti-proliferation activities on
all tested tumor cell lines, especially NCI-H1975 and HCC827, A431. Some of the tested
derivatives displayed very good inhibition of EGFR and HER2 enzyme inhibition.
Compounds 1a, 1d and 1v were identified with dual EGFR/HER2 better activities than
afatinib. The studies of these compounds on animal models were done. In vivo efficacy of 1d
was demonstrated on NCI-H1975 xenografts model. Compound 1d showed better results
compared to standard drug afatinib. Further investigations to identify the therapeutic candidate
in this quinazoline series are in progress and the results will be published elsewhere.
Acknowledgments
The authors would like to acknowledge financial support from Gusu Scientific Leadership
Program and Jiangsu Province Social development program, P. R. China. The authors are
thankful to Shanghai Medicilon Inc. for providing full biological assay services.
Supplementary data
Synthesis, analytical data and in vitro and in vivo bioassay methods are available.

References:
1
2
3
. Jordan J D, Landau E M, Iyengar R. Signaling of networks: the origin of the
multicellular multi-tasking. Cell 2000; 103: 193-200.
. Yarden Y, Sliwkowski M X. Untangling the ErbB signalling network. Nat. Rev. Mol.
Cell. Biol. 2001; 2: 127-137.
. Jackisch C, Lammers P, Jacobs, I. Evolving landscape of human epidermal growth
factor receptor 2-positive breast cancer treatment and the future of biosimilars. The
Breast 2017; 32; 199-216.
4
5
6
7
. Ross J S, Slodkowska E A, Symmans W F et al. The HER-2 receptor and breast
cancer: ten years of targeted anti-HER2 therapy and personalized medicine. Oncologist
2
009; 14: 320–68.
. Slamon D J, Godolphin W, Jones L A, et al. . Studies of the HER-2/neu proto-
oncogene in human breast and ovarian cancer. Science (Wash. DC) 1989; 244: 707–
7
12.
. Cox G, Vyberg M, Melgaard B, Askaa J, Oster A, O’Byrne K J. Herceptest: HER2
expression and gene amplification in non-small cell lung cancer. Int. J. Cancer 2001;
9
2: 480–483.
. Osman I, Scher H. I, Drobnjak M, Verbel D, Morris M, et al. HER-2/neu (p185)
protein expression in the natural or treated history of prostate cancer. Clin. Cancer.
Res., 2001; 7: 2643–2647.
8
9
. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel
therapeutic target. Ann Oncol. 2008; 19: 1523–9.
. Barker J, Gibson K. H, Grundy W, Godfrey A. A, et al. Studies leading to
theidentification of ZD1839 (Iressa™): an orally active, selective epidermal growth
factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg.
Med. Chem. Lett., 2001; 11: 1911-1914.
1
0. Wakeling E, Guy S P, Woodburn J R, Ashton S E, Curry B J, Barker A J, Gibson K
H. ZD1839 (Iressa) an orally active inhibitor of epidermal growth factor signaling with
potential for cancer therapy. Cancer Res. 2002; 62: 5749-5754.
1
1
1. Ganjoo K N, Wakelee H. Review of erlotinib in the treatment of advanced non-small
cell lung cancer. Biol. Targets Ther. 1 2007; 335-346
2. Burris H A. Dual kinase inhibition in the treatment of breast cancer: initial experience
with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004; 9: Suppl 3: 10–5.

1
1
3. Oxnard G R, Arcila M E, Chmielecki J, Ladanyi M, Miller V A, Pao W. New
strategies in overcoming acquired resistance to epidermal growth factor receptor
tyrosine kinase inhibitors in lung cancer. Clin. Cancer Res. 2011; 17: 5530-5537.
4. Pallis A, Briasoulis E, Linardou H, Papadimitriou C, Bafaloukos D, Kosmidis P,
Murray S. Mechanisms of Resistance to Epidermal Growth Factor Receptor Tyrosine
Kinase Inhibitors in Patients with Advanced Non-Small-Cell Lung Cancer: Clinical
and Molecular Considerations. Curr. Med. Chem. 2011; 18: 1613-1628.
1
1
5. Ohashi K, Maruvka Y. E, Michor F, Pao W. Epidermal growth factor receptor tyrosine
kinase inhibitor-resistant disease. J. Clin. Oncol. 2013; 31: 1070 − 1080.
6. Linardou H, Dahabreh I J, Kanaloupiti D. et al. Assessment of somatic k-RAS
mutations as a mechanism associated with resistance to EGFR-targeted agents: a
systematic review and meta-analysis of studies in advanced non-small-cell lung cancer
and metastatic colorectal cancer. Lancet Oncology, 2008; 9: 962-972.
1
1
1
2
7. Rulli E, Marabese M, Torri V. et al. Value of KRAS as prognostic or predictive
marker in NSCLC: results from the TAILOR trial. Annals of Oncology, 2015; 26:
2
079-2084.
8. Takeda M, Okamotob I, Nakagawaa K. Pooled safety analysis of EGFR-TKI
treatment for EGFR mutation-positive non-small cell lung cancer, Lung Cancer 2015;
8
8: 74-79.
9. Walter O, Tjin Tham Sjin R, Haringsma H J, Ohashi K, Sun J. et al. Discovery of a
Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance
in NSCLC. Cancer Discov. 2013; 3: 1404-1415.
0. Cross D A, Ashton S E, Ghiorghiu S, Eberlein C, Nebhan C A. et al AZD9291, an
irreversible EGFR TKI overcomes T790M mediated resistance to EGFR inhibitors
in lung cancer. Cancer Discov., 2014; 4: 1046-1061.
2
2
1. Dungo, R. T, Keating, G. M. Afatinib: First Global Approval. Drugs 2013; 73: 1503-
1
515.
2. Moll H P, Pranz K, Musteanu M, Grabner B, Hruschka N, Mohrherr J, Aigner P.
Afatinib restrains K-RAS–driven lung tumorigenesis. Science Translational Medicine.
Science
Translational
Medicine,
2018;
10:eaao2301
DOI:10.1126/scitraslmed.aao2301).
2
3. Minami Y, Shimamura T, Shah K., et al. The major lung cancer-derived mutants of
ERBB2 are oncogenic and are associated with sensitivity to the irreversible
EGFR/ERBB2 inhibitor HKI-272. Oncogene. 2007; 26 (34): 5023–7.

2
2
4. Reckamp K. L, Giaccone G, Camidge D R, Gadgeel S M, Khuri F R, Engelman J
A. et.al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible panHER
(
humanepidermal growth factor receptor) inhibitor, in patients with advanced non
small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer
014; 120: 1145-54.
2
5. Collisson E A, Campbell J D, Brooks A. N. et al. Comprehensive molecular profiling
of lung adenocarcinoma: The cancer genome atlas research network. Nature, 2014;
5
11: 543-550.
2
2
6. Hong J, Xu X, Le X, Zhang Z. Quinazoliine derivative preparation method therefor
and pharmaceutical composition and application thereof, Patent WO2016/23217
7. Khan I, Zaib S, Batool S, et al. Quinazolines and quinazolinones as ubiquitous
structural fragments in medicinal chemistry: An update on the development of
synthetic methods and pharmacological diversification. Bioorganic & Medicinal
Chemistry. 2016; 24(11):2361-2381
2
8. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2
inhibitor highly effective in preclinical lung cancer models. Oncogene.
2
008;27(34):4702-4711.

Graphical Abstract

Highlights


New quinazoline derivatives as dual EGFR/HER-2 inhibitors
In vitro evaluation of anti-proliferation activity of twenty four compounds on NCI
H1975, HCC 827, A431, MDA-MB-453 cell lines.



Identified dual EGFR/HER-2 inhibitors in nanomolar (nM) concentration.
Compounds 1a, 1d and 1v were found better EGFR/HER-2 inhibitors than afatinib.
In vivo efficacy of 1d was better than afatinib on nude mice NCI H1975 xenograft
tumor model.