Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors

Article abstract of DOI:10.1016/j.bmc.2019.05.043

Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1–A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC₅₀ = 4.5 nM), PI3Kβ (IC₅₀ = 4.5 nM), PI3Kγ (IC₅₀ = 4.5 nM), PI3Kδ (IC₅₀ = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC₅₀ values of 0.82 μM, 0.99 μM and 0.19 μM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKT^S473 in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.

Full text of DOI:10.1016/j.bmc.2019.05.043

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Accepted Manuscript
Alkylsulfonamide-containing quinazoline derivatives as potent and orally bio-
available PI3Ks inhibitors
Yuan-Yuan Hei, San-Qi Zhang, Yifan Feng, Jin Wang, Weiming Duan, Hao
Zhang, Shuai Mao, Haopeng Sun, Minhang Xin
PII:
S0968-0896(19)30488-2
https://doi.org/10.1016/j.bmc.2019.05.043
BMC 14930
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 March 2019
22 May 2019
28 May 2019
Please cite this article as: Hei, Y-Y., Zhang, S-Q., Feng, Y., Wang, J., Duan, W., Zhang, H., Mao, S., Sun, H., Xin,
M., Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors,
Bioorganic & Medicinal Chemistry (2019), doi: https://doi.org/10.1016/j.bmc.2019.05.043
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Alkylsulfonamide-containing quinazoline derivatives as potent and
orally bioavailable PI3Ks inhibitors
Yuan-Yuan Hei,† San-Qi Zhang,† Yifan Feng,† Jin Wang,‡ Weiming Duan,† Hao Zhang,† Shuai
Mao, † Haopeng Sun,§ Minhang Xin *,†
†
Department of Medicinal Chemistry, School of Pharmacy, Xian Jiaotong University, Xian,
Shaanxi, 710061, PR China
‡
Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University,
Xian, Shaanxi, 710061, PR China
§ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR
China
Corresponding Authors: (M. X.) Phone +86-29-82657040, Email: xmhcpu@163.com.
Abstract:
Phosphoinostide 3-kinases (PI3Ks) are regarded as promising targets for treatment
of various cancers due to their roles in regulating cell proliferation, differentiation,
migration, and survival. Here we report our efforts to develop potent and orally
bioavailable PI3K
inhibitors for the
treatment
of cancers. The
alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited
PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The
optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC50 = 4.5
nM)、PI3Kβ (IC50 = 4.5 nM)、PI3Kγ (IC50 = 4.5 nM)、PI3Kδ (IC50 = 4.5 nM) and
significantly inhibited the growth of HCT-116、MCF-7 and SU-DHL-6 cell lines with
IC50 values of 0.82 µM、0.99 µM and 0.19 µM, respectively. Western blot analysis
demonstrated A1 significantly suppressed the phosphorylation of AKTS473 in a
dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the
dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing
significant weight loss or toxicity.
1

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Keywords: quinazoline; PI3K inhibitor; drug design; antiproliferative effects;
anticancer agent
2

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1.Introduction
Phosphoinostide 3-kinases (PI3Ks) are a family of lipid kinases and central in
various cellular processes, such as cell proliferation, differentiation, migration, and
survival1. According to structural differences and substrate preferences, PI3Ks are
grouped into three classes: class I, class II and class III. Class I PI3Ks have been
extensively investigated and further classified into PI3Kα, PI3Kβ and PI3Kδ and
PI3Kγ2 . Among these, PI3Kα, PI3Kβ and PI3Kδ are individually comprised of a
catalytic p110 subunit (p110α, p110β and p110δ, respectively) heterodimerized with a
regulatory p85 subunit, while PI3Kγ isoform includes a catalytic p110γ and a
regulatory subunit, p101. There is abundant evidence showing that the different
isoforms of class I PI3K play different roles in tumors3-6. Consequently, PI3Ks are
regarded as promising targets for the development of novel broad-spectrum antitumor
agents.
Early reported small molecule PI3K inhibitors such as wortmannin (1)7 or
LY294002 (2)8 failed to advance into clinical evaluation because of the narrow
therapeutic index and severe toxicity. Subsequently, to reduce off-target toxicity and
increase efficacy, second generation PI3K inhibitors with more kinase selectivity were
pursued. Notably, the PI3K inhibitor copanlisib (BAY80-6946, 3)9,10 with excellent
potency against PI3Kα and PI3Kδ and significant inhibition of PI3Kβ and PI3Kγ, was
approved by the FDA for relapsed follicular lymphoma (FL) therapy in 201711. The
PI3Kδ selective inhibitor idelalisib (CAL-101, 4) and PI3Kδ/γ selective inhibitor
duvelisib (IPI-145, 5) has been approved for treatment of relapsed or refractory CLL
or SLL in 2014 and 2018, respectively12. Although these PI3K inhibitors have
established clinical proof-of-concept for treatment of hematological malignancies, it is
believed that PI3K inhibitors should also be able to demonstrate clinical benefit in
solid tumor therapy13-15. For example, several PI3K inhibitors, such as buparlisib
(NVP-BKM120, 6)16, omipalisib (GSK2126458, 7)17, dactolisib (BEZ235, 8)18 and
PF-04979064 (9)19 are being extensively investigated in the clinic against solid
tumors. Intriguingly, Novartis recently announced that their PI3Kα-specific inhibitor
3