Bioorganic & Medicinal Chemistry Letters
Identification of BR102910 as a selective fibroblast activation protein
(FAP) inhibitor
,
b
,
,*
Hui Jin Junga *, Eun Hye Nama, Jin Young Parka, Prithwish Ghoshb, In Su Kimb
a Research Center, Boryung Pharmaceuticals Co. Ltd., Ansan 15425, Republic of Korea
b School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Keywords:
Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both
exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is
greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its
restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option
for several diseases. In the present study, we described the structure–activity relationship of several synthesized
compounds against DPPIV and prolyl oligopeptidase (PREP). In particular, BR102910 (compound 24) showed
nanomolar potency and high selectivity. Moreover, the in vivo FAP inhibition study of BR102910 (compound 24)
using C57BL/6J mice demonstrated exceptional profiles and satisfactory FAP inhibition efficacy. Based on
excellent in vitro and in vivo profiles, the potential of BR102910 (compound 24) as a lead candidate for the
treatment of type 2 diabetes is considered.
Fibroblast activation protein
Fibroblast growth factor 21
FAP inhibitor
DPPIV
PREP
Fibroblast activation protein (FAP, FAP-
α
, separase) is a type II
sensitivity, fat browning, and glucose uptake. Therefore, the develop-
ment of FAP inhibitor could be a promising therapeutic approach for
type 2 diabetes alternative to the recombinant FGF21 therapies.10
With the growing interest on FAP inhibition in drug discovery,
various FAP inhibitors have been reported.11 For examples, a non-
selective inhibitor, Val-boroPro (1) reached up to the phase II clinical
trial for cancer treatment. However, it was withdrawn due to both safety
and efficacy issues (Fig. 2).12 Linagliptin (2) was clinically approved as a
DPPIV inhibitor though it shows significant FAP affinity.13 Recently,
ARI-3099 (3) with a boronic acid moiety was also found as a FAP in-
hibitor.14 The selectivity of this compound is more than 350-fold to-
wards FAP over PREP. The affinity of this compound is negligible for the
DPPs. It is noted that a dipeptide linker between pyrrolidine moiety and
heterocycle framework is very crucial for improved FAP affinity.14 In
fact, the installations on dipeptide linker led to the loss in potency to-
ward FAP and the increased selectivity for PREP rather than FAP. It was
also observed that addition of halo substituents (F and Cl) to the pyridine
ring improved potency against FAP.
transmembrane glycoprotein consisting of 760 amino acids, which is
inducible in cultured fibroblasts using the monoclonal antibody (mAb)
F19.1 It belongs to the family of post-proline dipeptidyl aminopepti-
dases, which mainly cleave peptide substrates after proline residues.2
Dipeptidyl peptidases (DPP2, DPP4, DPP8, DPP9) and prolyl oligo-
peptidases (PREP, POP) are also parts of this family.3 FAP is a serine
protease that has all of the activities of endopeptidase, and is known to
be highly expressed in various lesion tissues such as epithelial cancer,
cirrhosis and pulmonary fibrosis.4 Since FAP is mainly expressed in fi-
broblasts, it induces tumor development by cancer growth and the in-
vasion into normal tissues.5 Moreover, FAP is known to affect type 2
diabetes and obesity through the inactivation of FGF21 (fibroblast
growth factor 21) by the N- and C-terminal cleavage process.6 As shown
in Fig. 1, FGF21 is a hormone secreted from liver and adipose tissues to
regulate sugar and lipid metabolism.7 In the case of human FGF21, the
C-terminal portion of FGF21 is readily cleaved by FAP, and the biolog-
ical action of FGF21 is reduced by about 400 times.8 In addition, the
inactivation of FGF21 is involved in the accumulation of triglycerides
and improvement of inflammation in the liver. Therefore, it is expected
to be a crucial target for the treatment of non-alcoholic steatohepatitis
(NASH).9 Moreover, FGF21 is highly related with the control of insulin
Compound
4
containing
a
quinolinoylglycyl(2-cyano-4,4-
difluoropyrrolidine) backbone has been recognized as one of the most
potent FAP inhibitors.15 Notably, the preferential accommodation of 2-
cyanopyrrolidine moiety with minimal steric bulk in the FAP’s S1 pocket
* Corresponding authors at: Research Center, Boryung Pharmaceuticals Co. Ltd., Ansan 15425, Republic of Korea (H.J. Jung).
Received 21 December 2020; Received in revised form 23 January 2021; Accepted 30 January 2021
Available online 9 February 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.