The RET receptor tyrosine kinase is crucial for normal
development but also contributes to pathologies that reflect both
the loss and the gain of RET function. Activation of RET via
oncogenic mutations is involved in the development of several
human cancers.1,2 Activation of the RET point mutation is
associated with medullary thyroid carcinoma, and RET
rearrangement has been detected in papillary thyroid carcinoma.3
More importantly, RET fusion genes have also recently been
identified as driver oncogenes in non-small cell lung cancer
(NSCLC), with the associated fusion genes present in
approximately 1% to 2% of cases.4 The response of cabozantinib
as multikinase inhibitor targeting RET in RET fusion-positive
NSCLC provides early clinical validation of RET fusions as
drivers in lung cancers and suggests that RET inhibition may
represent a new treatment paradigm in this molecular cohort.5,6
Thus, the genetic alterations of RET are considered to be
promising targets for anticancer therapy.
inhibitor Vandetanib,8 VEGFR2/MET inhibitor Cabozantinib,9
VEGFR2/3 inhibitor Lenvatinib10 and multi-targeted inhibitor
Sorafenib11 have been approved for the treatment of thyroid
cancer. Ponatinib, a drug that is approved as a therapy for chronic
myelogenous leukemia and Philadelphia chromosome-positive
acute lymphoblastic leukemia, is a potent inhibitor of both
RETWT and Vandetanib/Cabozantinib-resistant RETV804M
kinase.12,13 The phase II clinical trials of ponatinib in treating non-
small cell lung carcinoma (NSCLC) harboring RET
rearrangements is now in progress, in treating advanced or
metastatic MTC has been terminated this year (Scheme 1).
Our group has previously synthesized an array of Ponatinib
analogues and identified that 4-chloro-3-(pyridin-3-ylethynyl)
benzamide derivative Hu1-117 exhibited potential RET enzyme
inhibitory activity with IC50 value of 2.5 ± 0.2 nM. Since five-
membered heteroaromatic rings is an ubiquitous and privileged
scaffold in drug design as a linker for its rigid structure, which
enable the substituent groups on it stretching to the appropriate
orientation, we envision that replacing the alkynyl linker of
compd Hu1-117 with different five-membered rings might keep
the RET inhibitory activity and generate the novel scaffold for
RET inhibitor. Herein, we reported the design, synthesis and
Due to the structural similarity between RET and other RTKs
in functional domains, especially the ATP-binding site, it has
been proved that many small-molecule RTK inhibitors (TKIs)
possess RET inhibitory activity.7 Among them, VEGFR2/EGFR
biological evaluation of these compounds.
* Corresponding author:
Yongzhou Hu, Phone/Fax:+86-571-8820-8460. E-mail:
14
then cyanided by Pd-catalyst with Zn(CN)2
to generate
compound 3. After addition reaction of 3 with hydroxylamine,
compound 4 was condensed with nicotinic acid to afford novel 3-
phenyl-5-pyridin-1,2,4-oxadiazole intermediate 5, which was
hydrolyzed and then condensed with 4-((4-methylpiperazin-1-
yl)methyl)-3-(trifluoromethyl)aniline to provide desired products
I-1 (Scheme 2, route A). 5-Phenyl-3-pyridin-1,2,4-oxadiazole
derivative II-1 and 1,3,4-oxadiazole-containing compound III-1
were prepared from similar route by the different cyclization in
Scheme 2 (route B and C).
Youhong Hu, Phone/Fax: +86-021-5080-5896. E-mail:
Meiyu Geng, Tel: +86-21-50806072, E-mail: mygeng@simm.ac.cn
Oxazole-containing intermediate 16 was obtained from 2-
bromo-1-(pyridin-3-yl)ethan-1-one (14) by the substitution with
2-chloro-5-(methoxycarbonyl)benzoic acid and BF3•Et2O-
catalyzed cyclization. After the hydrolysis of 16 and then
condensation
with
4-((4-methylpiperazin-1-yl)methyl)-3-
(trifluoromethyl)aniline, oxazole-containing compound IV-1 was
generated (Scheme 2, route D). Reversed oxazole-containing
compound V-1 was prepared by the key step of Pd(OAc)2-
catalyzed direct C-H activation of methyl 4-chloro-3-(oxazol-5-
yl)benzoate (19) with 3-iodopyridine 15 (Scheme 2, route E).
Scheme 1. Small-molecule RET inhibitors
Compounds containing 1,2,4-oxadiazole, 1,3,4-oxadiazole and
oxazole rings were synthesized by the following routes outlined
in Scheme 2. Commercially available 4-chloro-3-iodobenzoic
acid (1) as the starting material was esterified with MeOH and