Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors

Qing Tang,* Alex M. Aronov, David D. Deininger, Simon Giroux, David J. Lau ﬀ er, Pan Li, Jianglin Liang,

Innovations

Discovery of Potent, Selective Triazolothiadiazole-Containing c‑Met

Inhibitors

Kira McGinty, Steven Ronkin, Rebecca Swett, Nathan Waal, Diane Boucher, Pamella J. Ford,

and Cameron S. Moody

Cite This: ACS Med. Chem. Lett. 2021, 12, 955 −960

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sı Supporting Information

ABSTRACT: Herein, we report a novel series of highly potent

and selective triazolothiadiazole c-Met inhibitors. Starting with

molecule 5, we have applied structure-based drug design principles

to identify the triazolothiadiazole ring system. We successfully

replaced the metabolically unstable phenolic moiety with a

quinoline group. Further optimization around the 5,6 bicyclic

moiety led to the identiﬁcation of 21. Compound 21 suﬀered from

PDE3 selectivity issues and subsequent, structurally informed design led to the discovery of compound 23. Compound 23 has

exquisite kinase selectivity, excellent potency, favorable ADME proﬁle, and showed dose-dependent antitumor eﬃcacy in a SNU-5

gastric cancer xenograft model.

KEYWORDS: c-Met inhibitor, Structure-based drug design, PDE3

c-Met, also known as hepatocyte growth factor receptor

(

HGFR), is a member of the receptor tyrosine kinase (RTK)

family. The natural ligand of c-Met is the hepatocyte growth

factor (HGF), also known as scatter factor (SF). c-Met plays

an essential role in cellular signaling pathways involving

proliferation, invasion, migration, survival, angiogenesis, meta-

stasis, and drug resistance. Abnormal activation of the c-Met

pathway leads to tumor metastasis, invasion, and recurrence.

Overexpression of c-Met and/or HGF is often associated with

a large number of human cancers such as breast, lung, liver,

kidney, stomach, and brain. Therefore, c-Met has been

recognized as an attractive target for the development of

cancer therapies and was of considerable interest to us during

our past eﬀort in oncology.

In the past two decades, progress has been made toward the

development of small-molecule c-Met inhibitors. There are

,9,12

Figure 1. Type I and type II c-Met inhibitors.

two types of ATP-competitive c-Met inhibitors based on

binding modes (Figure 1). Type 1 inhibitors interact with the

hinge residue Met1160 within the U-shaped ATP-binding

solvent-accessible area. Those most known type II inhibitors

pocket and also interact with Tyr1230 via a π−π stacking

potently inhibit VEGFR as well as other homological kinases.

Cabozantinib (4) is a type II c-Met inhibitor approved by the

FDA. Type II inhibitors often have a broader inhibition

interaction. In general, type 1 c-Met inhibitors have good

kinase selectivity. Crizotinib (1) is a type 1 inhibitor approved

by the U.S. Food and Drug Administration (FDA), that

inhibits ALK, Ros1, and c-Met. Additionally, savolitinib (2)

Received: February 18, 2021

Accepted: May 11, 2021

Published: May 24, 2021

is another type 1 c-Met inhibitor displaying enhanced kinase

selectivity which has shown fewer side eﬀects in clinical trials.

Capmatinib (3) is a newly approved ATP-competitive and

selective c-Met inhibitor for the treatment of advanced non-

small cell lung cancer. Type II inhibitors bind at the deep

hydrophobic back pocket between the hinge residue and the

2021 American Chemical Society

ACS Med. Chem. Lett. 2021, 12, 955−960

ACS Medicinal Chemistry Letters

Innovations

spectrum which may help in overcoming acquired resistance to

type I inhibitors, but they also have tolerability issues in clinical

settings.

pharmacokinetics (PK) in rats (data not shown). The

compound 8 revealed lower c-Met kinase activity. Triazolo-

thiadiazole 9 (K = 400 nM) was signiﬁcantly less potent than

Herein, we describe the discovery and optimization of a new

series of triazolothiadiazole compounds as potent and selective

c-Met inhibitors. Structure-based drug design was used to

guide us during lead optimization. Improvements on potency,

metabolic stability, and selectivity versus PDE3 are discussed.

Finally, we provide in vivo eﬃcacy data on a relevant tumor

model.

compound 5 (K = 60 nM); however, compound 10 (K = 30

nM) demonstrated good potency. The scarcity of the

triazolothiadizole bicyclic system in the literature and the

promising potency prompted us to explore this subseries

further. The cocrystal complex of triazolothiadiazole 10 bound

to the c-Met kinase domain is shown in Figure 2A. A hydrogen

bond is formed between the phenolic oxygen atom and the

backbone NH of Met1160. The binding mode also suggests a

π-stacking interaction between the triazolothiadiazole core and

Tyr1230 and a hydrogen bond interaction between the N1 of

the core and the backbone NH of Asp1222. In this co-complex

structure, we also observed an interaction between the sulfur of

the core ring with the carbonyl of Arg1208. Additionally, the

N-linker of compound 10 is unexpectedly engaged in a

hydrogen bond to the backbone carbonyl Arg1208.

In an eﬀort to identify a potent, selective c-Met inhibitor, we

focus on a series of triazolotriazines that showed promising c-

Met inhibition activity. One of the promising compounds, 5

(

from a Sugen patent), displayed c-Met enzymatic K and

cellular IC ’s of 60 and 32 nM, respectively (Table 1). We

began our exploration by systematic replacements of the

triazolotriazine core with diﬀerent [5,5]- and [5,6]-bicyclic

cores (Table 1).

Given that the binding mode, as reﬂected by the cocrystal

structure, shows a key interaction between the phenolic moiety

and c-Met and that we also observed glucuronidation

metabolites with these phenolic compounds (data not

Table 1. Exploration of [5,5]- and [5,6]-Bicyclic

Triazolotriazine Replacements

shown), we next investigated if either modiﬁcation on the

phenol would slow down metabolism or if isosteric phenolic

replacements would alleviate undesirable metabolism. As

shown in Table 2, moving the hydroxyl group from the 4-

position of 11 to the 3-position of 12 disrupted the hydrogen

bond interaction, and consequently, the c-Met inhibitory

potency dropped by more than 20-fold. Capping the hydroxyl

groups with a 1,3-dioxolane group (13) also reduced the

potency signiﬁcantly. Introduction of an ortho-ﬂuoro atom

(

14) or an ortho-chloro atom (15) also caused a potency

erosion. As the nitrogen atoms of quinolines and azaindoles are

often used as the hinge binding elements in kinase programs,

alternative aromatic groups as potential hydrogen bond

donors were explored. Although the azaindole as the hinge

binder 16 caused a sharp potency drop, compound 17 was

made and demonstrated good potency and a lipophilic

eﬃciency (c-Met lipE = 3.9) comparable to those of our

initial phenolic compound 11. An overlay of quinoline 17 with

phenol 11 is shown in Figure 2B. The overlay indicates that the

nitrogen atom of the quinoline ring of 17 occupies the same

position of the phenolic oxygen of 11. Both formed similar

hydrogen bonds with Met1160.

Although compounds 13−17 showed moderate rat

hepatocyte stability, high clearances and short half-lives were

observed in rat PK experiments (Supporting Information ).

These data suggested that lower clearance may be obtained by

decreasing the lipophilicity of these compounds. Some of our

early structure−activity relationship (SAR) studies (not

shown) indicated that aromatic substitutions at C6 of

triazolothiadiazoles were well tolerated, and we believed that

modiﬁcations of the C6 aromatic groups could modulate the π-

stacking interaction with Tyr1230 allowing for increased

potency and improved metabolic stability. In this regard, we

were pleased to ﬁnd that heteroaromatics such as pyrazole

analogue 18 could maintain potency while increasing our

lipophilic eﬃciency above 5. More importantly, 18 demon-

strated improved rat clearance to 24.5 mL/min/kg and a half-

life as 1.1 h (Supporting Information).

Inhibition of cMet kinase activity (K ) was determinated by standard

radiometric assay. The cell IC₅₀was determinated using MKN

gastric carcinoma. LipE value calculated from c-Met pK

Five structurally relevant [5,6]- and [5,5]-systems were

evaluated for their c-Met inhibition activity (Table 1).

Although promising c-Met activity was observed with

compound 6 (K = 200 nM) and compound 7 (K = 80

nM), these two scaﬀolds were deprioritized quickly due to

poor in vitro metabolic stability and poor in vivo

Since the methylene linker between the quinoline ring and

the triazolothiadiazole bicyclic system is easily oxidized by

CYP-mediated metabolism, the introduction of small groups

ACS Medicinal Chemistry Letters

ACS Med. Chem. Lett. 2021, 12, 955−960

Innovations

Table 2. Modiﬁcations of the Phenolic Moiety

Inhibition constant (K ) and cellular IC were determined as

described in the Supporting Information.

that the methylene linker is adjacent to a pocket composed of

Leu1157 and Lys1110, we envisioned that small hydrophobic

substitutions might occupy the pocket and enhance kinase

inhibition potency. Monomethyl substitution 19 led to a 3-fold

improvement in cellular c-Met inhibition. More signiﬁcantly,

0 and 21 have a 15-fold and 4.5-fold diﬀerence in the activity

of enzymatic K and cellular IC , respectively, thus indicating

the importance of the stereochemistry of the linker substituent.

The enantiomerically pure compounds 20 and 21 were both

crystallized in c-Met with the primary structural diﬀerence

being the chirality at the methylene linker. The (S)-isomer

places the methyl group further into a hydrophobic region of

the protein ﬂanked by Leu1157, Ala1226, and Lys1110.

Additionally, this chiral change shifts the core by ∼0.7 Å

toward the entrance of the pocket, leading to ideal distance

between Met 1160 and the quinoline nitrogen and moving the

methylpyrazole moiety further toward the solvent front while

leaving the observed hydrogen bond to Asp1222 unchanged.

The overlay is based on the superposition of our internal

crystal structures with emphasis on the pocket residues (Figure

C). The (S)-isomer projects more deeply into the hydro-

phobic region of this pocket as shown, while not being so

bulky as to clash with nearby pocket residues.

Generally speaking, all the compounds in Table 3 have low

unbound human and mouse intrinsic clearances, which

indicated good physical properties and developability.

The inhibition of c-Met kinase activity was determined in a

radiometric assay by a series of titration at 35 μM of ATP. The

degree of c-Met inhibition varied linearly with the ATP

concentration, indicating competitive inhibition. Compound

Figure 2. Compound binding modes in the c-Met ATP site pocket

and key interactions. (A) Crystal structure of 10 (green). (B) Overlay

of quinoline compound 17 (purple) and phenol compound 11

1 selectively inhibits c-Met kinase with K = 0.025 μM.

Generally speaking, all the compounds from the triazolothia-

diazole series have shown good kinase selectivity against our

in-house panel of 15 kinases including FLT3, GSK3, JAK2,

(

green). (C) Crystal structures of compound 20 (purple) and 21

green) superimposed.

KDR, SRC, SKY, and PI3K with K > 4 μM. In addition,

compound 21 demonstrates <50% inhibition (at 2 μM) against

that can potentially block metabolism was investigated. Given

that the cocrystal of compound 17 with c-Met kinase indicated

all 50 kinases included in the upstate/Millipore panel. In a

ACS Med. Chem. Lett. 2021, 12, 955−960

ACS Medicinal Chemistry Letters

shown in Figure 3 . Compound 21 superimposes well with the

Innovations

Table 3. Substitutions on the Methylene Linker

clogD⁷^.⁴

compd

R₃, R₄

(H,H)

rac-(Me, H)

R-(H, Me)

S-(Me, H)

c-Met K (μM)

SNU-5 IC₅₀(μM)

HepsCl u human, mouse (μL/min/10 cells)

lipE (c-Met)

int

0.04

0.05

0.3

0.08

0.03

0.09

0.02

4.8, 6.2

3.2, 7.4

5.8, 7.0

5.1, 7.2

2.1

2.6

5.3

4.7

3.9

5.1

0.02

broader panel of 67 receptors, compound 21 was found to

inhibit PDE3 with an IC₅₀of 0.5 μM (Supporting

Information). Since PDE3 expression is high in cardiac and

Table 4. Selectivity against PDE3 for Compounds 20−25

vascular myocytes and PDE3 inhibition may cause oﬀ-target

cardiovascular eﬀects, we decided to investigate the selectivity

data against PDE3 for some existing compounds within this

series (20 and 21) as well as the design of novel analogues

aimed at gaining an understanding of the structural require-

ments to achieve selectivity against PDE3. We overlaid

compound 21 with Merck PDE 3 inhibitor “MERCK1”, as

Figure 3. Overlay of 21 (A) and 23 (B) with the published MerckI

PDE3 inhibitor (green).

published PDE3 inhibitor MERCK1 in a low energy

conformation. Hydrogen bonding to Gln988 and hydrophobic

contacts to Ile995 and Phe959 are maintained in the PDE3

active site.

As shown in the Table 4, the stereochemistry at the

methylene linker substitution has an inﬂuence on the PDE3

selectivity with the (R)-isomers (20 and 24) showing

selectivity ratios of 95 and 67 as opposed to ratios of 25 and

3 for their (S)-counterparts, compounds 21 and 25.

Introduction of the gem-diﬂuoro linker (data not shown) is

well tolerated for cMet activity while also improving the cMet/

PDE3 selectivity ratio. With this information in mind, we

decided to investigate the possibility of including a NH spacer

between the triazolothiadiazole and the C6 bottom pyrazole

ring. Much to our delight, compound 22 oﬀered 5 nM cellular

potency and a PDE3 selectivity ratio of 600. By combining the

gem-diﬂuoro linker and the C6 space, compound 23, which

was found to be very potent with 4 nM potency and to have

over 2000-fold selectivity against PDE3, was less able to

replicate the binding mode of MERCK1. The addition of the

nitrogen linker between the core and the methyl pyrazole

makes the interaction with Gln988 less conserved in low

energy docking poses, potentially removing its ability to make a

stable hydrogen bond at that location. Additionally, the proton

on the nitrogen linker has no nearby hydrogen bonding

partners and a desolvation cost would apply to place it against

the nearby hydrophobic surface. It is interesting to note that a

similar increase in cellular potency was observed with the

introduction of a methyl group on the C3 pyrazole. Despite

showing high potency in SNU-5 (IC₅₀of 3 nM each),

compounds 24 and 25 retained potency against PDE3 and

therefore have very low selectivity windows and were not

pursued further. Docking 23 in the c-Met protein conﬁrmed all

ACS Med. Chem. Lett. 2021, 12, 955−960

ACS Medicinal Chemistry Letters

Innovations

key interactions: hydrogen bonding with Met1160, π−π

of structure-based drug design allowed us to (1) identify the

quinoline group as a metabolically stable hinge binding

element and (2) dial out the PDE3 liability of our lead

triazolothiadiazole scaﬀold. Compound 23 has exquisite kinase

selectivity, excellent potency, and favorable ADME and PK

proﬁles and showed dose-dependent antitumor eﬃcacy in vivo.

stacking with Tyr1230, and NH linker with Arg1208

The Supporting Information is available free of charge at

Supporting Information).

Given its very high c-Met potency and high PDE3

selectivity, compound 23 was evaluated in pharmacokinetic

studies in multiple species (Table 5). Overall, 23 has favorable

Table 5. Multiple-Species PK Data for Compound 23

ASSOCIATED CONTENT

■

rat

mouse

dog

monkey

sı Supporting Information

https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00094.

Cl (mL/min/kg)

V_s_s(L/g)

0.70

1.4

0.15

0.60

1.0

1.8

4.8

100

1.6

3.6

1.3

9.9

1.2

2.0

T₁_/₂(h)

C_m_a_x(μg/mL)

Experimental procedures for the key compounds,

biological assay information, kinase selectivity proﬁles,

statistical analysis of compound 23 in SNU-5 xenograft

model, selective compound rat IV PK, in vitro

pharmacokinetic data of compounds 21 and 23 and

computational modeling information (PDF)

AUC (μg/h/mL)

Parameters obtained after IV dosing. Parameters obtained after PO

dosing. IV dosing: 0.9 mpk; PO dosing: 2.6 mpk with 0.5% MC/

.1% Tween 80 formulation. IV dosing: 0.8 mpk; PO dosing: 13

mpk with 0.5% MC/0.1% Tween 80 formulation. IV dosing: 0.8

mpk; PO dosing: 12 mpk with 30% PG/10%Solutol/1% HPMC-AS

formulation, IV dosing: 0.9 mpk.

AUTHOR INFORMATION

■

pharmacokinetics displaying moderate total clearance and

volumes of distribution across all species tested. Following oral

dosing of 10 mpk of compound 23 to rat and dog, respectively,

the compound was absorbed rapidly in the rat with C_m_a_x

occurring at 0.5 h, but in the dog the C_m_a_xoccurred at 1.7 h.

Exposure in the dog was 2−3-fold higher than that in the rat at

this nominal dose. The bioavailability was moderate in the rat

and high in the dog.

We next investigated compound 23 in the ectopic human

SNU-5 gastric cancer xenograft model, which has ampliﬁed c-

Met acitivity. The SNU-5 model is a tumor model with

ampliﬁed c-Met.

Corresponding Author

Qing Tang − Vertex Pharmaceuticals Incorporated, Boston,

Massachusetts 02210, United States; orcid.org/0000-

0002-2663-0962 ; Phone: 617-3416738;

Email: qing_tang@vrtx.com

Authors

Alex M. Aronov − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

David D. Deininger − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Simon Giroux − Vertex Pharmaceuticals Incorporated, Boston,

Massachusetts 02210, United States; orcid.org/0000-

As shown in Figure 4, 23 induced tumor regression in a

dose-dependent manner with complete regression at 30 mpk

0003-1499-2576

David J. Lauﬀer − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Pan Li − Vertex Pharmaceuticals Incorporated, Boston,

Massachusetts 02210, United States

Jianglin Liang − Vertex Pharmaceuticals Incorporated, Boston,

Massachusetts 02210, United States; orcid.org/0000-

0002-1507-071X

Kira McGinty − Vertex Pharmaceuticals Incorporated, Boston,

Massachusetts 02210, United States

Steven Ronkin − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Rebecca Swett − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Nathan Waal − Vertex Pharmaceuticals Incorporated, Boston,

Massachusetts 02210, United States

Diane Boucher − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Pamella J. Ford − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Cameron S. Moody − Vertex Pharmaceuticals Incorporated,

Boston, Massachusetts 02210, United States

Figure 4. In vivo eﬃcacy of 23 in the ectopic human SNU-5 gastric

cancer xenograft model in SCID mice. (A) Tumor growth curve; (B)

change in body weight.

(

T/Ti of −23.9%) after 38 days post implantation. At the

lower dose groups (3 and 10 mpk), signiﬁcant tumor growth

inhibition was observed compared to controls (T/C of 16.6

and 54.2). Additionally, the compound was well-tolerated, with

mice showing no signiﬁcant body weight loss with 30 mpk

during the dosing regimen (Figure 4B). 23 alleviated the body

weight loss commonly observed in untreated SNU-5 tumor-

bearing SCID mice. These results, combined with favorable

pharmacokinetic proﬁles across species, allowed advancement

of 23 as a tool compound for preclinical studies.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acsmedchemlett.1c00094

Notes

Herein, we have reported a novel series of highly potent and

selective triazolothiadiazole c-Met inhibitors. The judicious use

The authors declare no competing ﬁnancial interest.

ACS Med. Chem. Lett. 2021, 12, 955−960

ACS Medicinal Chemistry Letters

S.; Said, E. The c-Met inhibitor Capmatinib alleviates acetaminophen

Innovations

(

9) (a) Saad, K. M.; Shaker, M. E.; Shaaban, A. A.; Abdelrahman, R.

ACKNOWLEDGMENTS

■

induced. Int. Immunopharmacol. 2020, 81, 106292. (b) Kim, S.; Kim,

T. M.; Kim, D. M.; Kim, S.; Kim, M.; Ahn, Y. O.; Keam, B.; Heo, D.

S. Acquired resistance of cMet inhibitor Capmatinib. Cancer Res.

Treat. 2019, 51 (3), 951−962.

The authors gratefully acknowledge Dr. Arjun Narayanan for

modeling work and Dr. Caroline Chandra Tjin for reviewing

and providing comments on the paper.

ABBREVIATIONS

(10) Schroeder, G. M.; An, Y.; Cai, Z.-W.; Chen, X.-T.; Clark, C.;

Cornelius, L. A. M.; Dai, J.; Gullo-Brown, J.; Gupta, A.; Henley, B.;

Hunt, J. T.; Jeyaseelan, R.; Kamath, A.; Kim, K.; Lippy, J.; Lombardo,

L. J.; Manne, V.; Oppenheimer, S.; Sack, J. S.; Schmidt, R. J.; Shen,

G.; Stefanski, K.; Tokarski, J. S.; Trainor, G. L.; Wautlet, B. S.; Wei,

D.; Williams, D. K.; Zhang, Y.; Zhang, Y.; Fargnoli, J.; Borzilleri, R. M.

Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophen-

yl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxa-

mide (BMS-777607), a selective and orally efficacious inhibitor of the

Met kinase superfamily. J. Med. Chem. 2009, 52, 1251−1254.

■

cMet, mesenchymal-to-epithelial transition factor; HGF,

hepatocyte growth factor; HGFR, hepatocyte growth factor

receptor; RTK, receptor tyrosine kinase; SF, scatter factor;

PDE, pan-phosphodiesterase

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