Bioorganic & Medicinal Chemistry Letters
Substituted diaryl ether compounds as retinoic acid-related orphan
Receptor-γt (RORγt) agonists
a
,
*
a
a
a
a
Zheming Ruan , Peter K. Park , Donna Wei , Ashok Purandare , Honghe Wan ,
a
a
a
a
b
Daniel O’Malley , Sylwia Stachura , Heidi Perez , Cullen L. Cavallaro , Carolyn A. Weigelt ,
b
b
b
c
c
John S. Sack , Max Ruzanov , Javed Khan , Murali Gururajan , Jessica J. Wong ,
c
d
d
e
e
f
Yanling Huang , Melissa Yarde , Zhuyin Li , Cliff Chen , Huadong Sun , Virna Borowski ,
f
d
d
a
a
Jenny H. Xie , Monique Anthony , Michele Agler , Brian E. Fink , Lalgudi S. Harikrishnan
a
Department of Chemistry, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA
b
Molecular Structure & Design, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA
c
Immuno-Oncology Small Molecule Biology, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA
d
Lead Discovery & Optimization, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA
e
Preclinical Candidate Optimization, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA
f
In vivo Pharmacology, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt
RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead
optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive
SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved
pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38
syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.
RORγt
RORgt
(
ROR gamma
Retinoic acid related-orphan receptor
Th 17 cells and IL-17
The Retinoic acid-related Orphan Receptor γt (RORγt), an isoform of
ROR gamma, is a nuclear receptor (NR) transcription factor.1 Mainly
expressed in T cells, it acts as a master control switch. In particular, in
2a clinical trial to treat patients with solid tumors (National Clinical
,2
12
Trial Numbers: NCT02929862 and NCT03396497). It has demon-
strated single agent therapeutic activity in multiple animal models of
cancer.
response to ligand binding, it activates transcription of IL-17A and IL-
,4
1
7F genes and is a regulator of Th17 cell differentiation.3 High levels
As part of an effort to discover novel RORγt agonists, we took
advantage of existing high throughput screening data previously
of IL-17 have been associated with improved prognosis in certain can-
5
13
cers. RORγt modulates expression of genes perating in pathways that
generated for an inverse agonist program. Diaryl ether 1 was identified
6
enhance immunity and decrease immune suppression. Therefore,
with a potency that was modest (RORγt-GAL4 EC50 = 332 nM), but
exceeded that of desmosterol (RORγt-GAL4 EC50 = 5500 nM), a putative
endogenous agonist.13 An X-ray co-crystal structure with the RORγt-
Ligand Binding Domain (LBD) was obtained (Fig. 1). The isopropyl
methoxyphenyl ring of 1 packs against Trp317, His479, and Tyr502,
stabilizing the agonist conformation of helix 12. Such stabilization has
been reported to enhance the recruitment of the coactivator SRC pep-
RORγt is a potential target not only for treatment of Th17 cell-mediated
autoimmune diseases, but also for cancer immune therapy. Recent
studies have indicated that RORγt agonists may elicit a novel antitumor
mechanism via activation of Th17 and Tc17 cells, enhancing the
expression of costimulatory receptors and increasing critical chemo-
kines and cytokines for T cell mediated effect.7 In addition, enhanced
antitumor immunity has been shown with adoptive transfer of CD8 +
,8
tide.14 The dichloro phenyl ring engages in
π
- stacking with Phe378,
π
Tc17 cells in the B16 mouse tumor model.9
–11
and the hydroxyl group hydrogen bonds to a network of water molecules
in the proximal region of the ligand binding pocket.
Only a few RORγt agonists have been reported in the literature. The
most advanced compound is LYC-55716, which is under study in a Phase
Compound 1 was originally identified as a thyroid receptor (TR)
*
Received 23 October 2020; Received in revised form 18 December 2020; Accepted 31 December 2020
Available online 8 January 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.