Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.06.008

Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry. The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro. The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction. The work highlights the some of the key challenges in designing effective protein-protein inhibitors for the Bcl-2 class of proteins.

Full text of DOI:10.1016/j.bmcl.2019.06.008

Accepted Manuscript
Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors
Bruce Follows, Shawn Fessler, Timm Baumeister, Ann-Marie Campbell, Mary
Margaret Zablocki, Hongbin Li, Deepali Gotur, Zhongguo Wang, Xiaozhang
Zheng, Lisa Molz, Cokey Nguyen, Torsten Herbertz, Liann Wang, Kenneth Bair
PII:
S0960-894X(19)30375-0
https://doi.org/10.1016/j.bmcl.2019.06.008
BMCL 26486
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 March 2019
2 June 2019
5 June 2019
Please cite this article as: Follows, B., Fessler, S., Baumeister, T., Campbell, A-M., Margaret Zablocki, M., Li, H.,
Gotur, D., Wang, Z., Zheng, X., Molz, L., Nguyen, C., Herbertz, T., Wang, L., Bair, K., Discovery of novel biaryl
sulfonamide based Mcl-1 inhibitors, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/
j.bmcl.2019.06.008
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Graphical Abstract
Leave this area blank for abstract info.
Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors
Bruce Follows, Shawn Fessler, Timm Baumeister, Ann-Marie Campbell, Mary Margaret Zablocki, Hongbin Li,
Deepali Gotur, Zhongguo Wang, Xiaozhang Zheng, Lisa Molz, Cokey Nguyen, Torsten Herbertz, Liann Wang,
Kenneth Bair

Bioorganic & Medicinal Chemistry Letters
Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors
Bruce Follows,*,a Shawn Fessler,a Timm Baumeister,a Ann-Marie Campbell,b Mary Margaret Zablocki,b
Hongbin Li,b Deepali Gotur,a Zhongguo Wang,a Xiaozhang Zheng,a Lisa Molz,a Cokey Nguyen,a Torsten
Herbertz,a Liann Wang,a Kenneth Baira
aFORMA Therapeutics, 500 Arsenal Street, Suite 100, Watertown, MA 02472, USA
bFORMA Therapeutics, 35 Northeast Industrial Road, Branford, CT 06405, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human
solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated
resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry.
The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple
biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by
SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro.
The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding
pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction.
The work highlights the some of the key challenges in designing effective protein-protein inhibitors for
the Bcl-2 class of proteins.
Keywords:
Mcl-1
Myeloid cell leukemia-1
inhibitors
small molecule
BH3-mimetic
2016 Elsevier Ltd. All rights reserved.
The Bcl-2 class of proteins, which is comprised of the anti-
apoptotic (Mcl-1, Bcl-2, Bcl-xl, Bcl-w, Bfl-1/A1) and pro-
apoptotic or BH3 proteins (Bim, Bid, Bad, Noxa) play critical
roles in maintaining cellular homeostasis during normal cell
differentiation during embryonic tissue development and
remodeling. During this process, unwanted cells are removed
through apoptosis as regulated by the intrinsic cell death
pathway.1 Mcl-1 functions as a negative regulator in this
process, and like other anti-apoptotic proteins, sequesters the
mediators or “apoptosis effectors” of the cell death response,
BAX and BAK. When left unbound, BAK and BAX localize in
the mitocondrial membrane to induce the release of caspases
ultimately resulting in apoptosis.2-4 Other pro-apoptotic BH3
proteins (Bid, Bim and Bad, Noxa, etc.) known as “apoptosis
initiators” form tightly bound BH3-Mcl-1(Bcl-2,) complexes that
effectively liberate BAK and BAX to tip the balance toward cell-
death.5
vincristine8, paclitaxel,8 or gemcitabine.7 Bcl-2 inhibitors in the
clinic show efficacy in lymphoid tumors presumed to be Bcl-2
dependent where the mechanism of action is direct competition
with anti-apoptotic proteins. The first in class intravenous drug
ABT-737 and ABT-263, an orally available, dual Bcl-2/Bcl-XL
inhibitor, were evaluated as therapies in small-cell lung cancer
and B-cell malignancies.9 The dual inhibitor caused dose limiting
toxicity (thrombocytopenia) attributed to an on-target effect of
Bcl-XL inhibition. A selective Bcl-2 inhibitor ABT-19910 offered
tolerability advantages over its predecessors and was approved
by the US FDA for patients with chronic lymphocytic leukemia
carrying a 17-p deletion. Limited efficacy has also been observed
in certain instances of Mcl-1 overexpression.2, 11
While a number of small molecule Mcl-1 inhibitors12-17 as
well as peptide related BH3 protein mimetics18-21 have been
reported, three Mcl-1 specific inhibitors have entered clinical
14
trials.12,
A Phase 1 study with Novartis’ MIK665 to treat
Much evidence supports targeting Mcl-1 for the treatment of
human cancer. A recent review reports that amplified levels of
Mcl-1 occur in numerous haematological and solid tumor tissues
including lung, breast, prostate, pancreatic, ovarian, cervical and
melanoma.6 Furthermore, many of these Mcl-1 overexpressing
tissues exhibit tumor growth inhibition and cell death upon RNA
silencing.6 In pancreatic cancer cell lines, RNAi mediated tumor
growth reduction was observed both in vitro and in mouse
xenograft models further validating Mcl-1 as an oncology target.7
patients with refractory or relapsed lymphoma or multiple
myeloma will reach completion by April of 2020. Amgen
initiated clinical studies with AMG-176, currently recruiting
patients with relapsed or refractory disease states of multiple
myeloma or acute myeloid leukemia. A newer compound,
AMG-397, entered Phase I trials to treat patients with multiple
myeloma, non-hodgkin’s lymphoma or acute myeloid leukemia.
These selective, reversible small molecules inhibitors represent
first in class drugs capable of disrupting Mcl-1 from high affinity
BH3 binding proteins in vivo. Alternative routes of inhibition
have been reported including inactivation of Mcl-1 through a
covalent bond with a noncatalytic lysine side chain.22 Thus,
In the clinic, Mcl-1 overexpression has been observed as a
primary resistance mechanism following treatment with

much effort is directed toward the development of Mcl-1
inhibitors as drugs to treat cancer.
Herein we describe the discovery of novel (double digit
nanomolar), small molecule inhibitors of the Mcl-1/BH3 protein-
protein interaction.
Hit identification was carried out using a high-throughput
screening campaign which identified several chemotypes as
starting points (Figure 1). Our testing paradigm incorporated
validation activities run in parallel to expedite the early validation
stage. While routine re-testing of purified material was
conducted, exploratory libraries around each chemical series
established preliminary SAR trends. Our high-throughput
synthesis platform and screening capabilities were subsequently
useful in differentiating initial leads. A fluorescence polarization
assay was used to determine the IC50 values required to disrupt
the recombinant human Mcl-1 and a FITSI labeled BID protein.23
Several of the initial hit series, including the tetrahydroquinolines
(1), pyrroles (2) and pyrazolidinones (3) were quickly eliminated
during hit validation due to uninterpretable SAR upon re-
synthesis of the actives and near neighbors. While the actual
mechanism of inhibition is unknown, examples from the
literature are often the result of compound aggregation,
interference in the light detection format or compound
reactivity.24-25
Figure 3. quantitative densitometry of Western blot normalized to the
control
Several synthetic libraries based upon 4 were prepared to
systematically interrogate SAR around the molecule (Figure 4).
Left-hand modifications (Library A; Table 1) revealed that
variations to the size, polarity or substitution pattern around the
ring were detrimental to activity. Deleting either the 2-Cl
(8)
or the 5-CF3 (7) group resulted in a complete loss of
activity. Incorporating polarity by the introduction of a
heterocycle (9) or appending polar groups on the phenyl ring
system (10, 12) also resulted in an abrogation of activity shown
by representative examples in Table 1.
Among the original HTS hits, a pull-down experiment
indicated that 4 disrupts the BH3/Mcl-1 binding interaction.
Western blot analysis revealed a dose dependent reduction in the
levels of the Mcl-1/tBid complex, purportedly at the Mcl-1/BH3
interface. The protein levels at 3 inhibitor concentration were
quantified and normalized to the control as depicted in Figure 3.
Taken together, the data suggested 4 was a competitive,
reversible Mcl-1 inhibitor warranting further medicinal chemistry
optimization.
The most active compounds with single digit micromolar
activity had either methyl or chloro groups in the ortho position.
Modifications on the right-hand side of the molecule (Library B;
Table 2) revealed several prominent SAR trends: Expanding the
size of the ortho group or removing it led to potency losses.
Within the set of ortho -Cl and -Me compounds, additional
para/meta substitution neither helped nor hindered biochemical
activity given that compounds bearing different functionality at
the meta/ortho positions were equally potent as evident by
thiophene (20, IC50 = 1.9 M) and cyclic lactam (26, IC50 = 1.8
M).
Figure 1. Actives from HTS screen
Figure 4. Exploratory library design from initial HTS hit. Library A =
iterative changes on the left-hand side; Library B = iterative changes on the
right-hand side; Library C = addition of functionality on the sulfonamide
nitrogen.
Figure 2. Western blot of Mcl-1/tBid complex after treatment with 0, 3,
10 and 30 M concentration of 4.

Table 1. SAR summary of Library A
Table 2. SAR Summary of Library B
Exploratory targets were prepared from commercially available
starting materials using three general reaction conditions as
shown in Scheme 1: 1) Sulfonylation from the sulfonyl chloride
and corresponding aniline (4-27) conducted in pyridine and
dichloromethane; 2) Reductive amination using sodium
borohydride and acetic acid in dichloroethane (30, 31); 3)
Alkylation reactions from an alkyl halide and phenol/thiophenol
using potassium carbonate or cesium carbonate as the base in
DMF (29, 32, 33). Sulfide 29 was oxidized with mCPBA to
afford sulfoxide 28. Thiophene analogues 34-39, 43 were
prepared in three steps starting with sulfonamide formation
between 2-chloro-5-(trifluoromethyl)aniline and methyl 5-
(chlorosulfonyl)-4-methylthiophene-2-carboxylate (Scheme 2).
The product was hydrolyzed with NaOH in MeOH-THF-water
and treated in a subsequent step with the corresponding amine
under BOP coupling conditions to give the desired products. A
modification of this sequence was used to prepare acids 40-42
and 44-57 in which an additional hydrolysis step was added after
the peptide coupling with an amino ester. Amides 63 and 64 as
well as acylsulfonamides 61 and 62 were derived from reactions
with chiral carboxylic acid 41 as shown in Scheme 2.
To probe the central linker portion of 2, a small set of
derivatives was prepared including the reverse sulfonamide and 2
atom linkers comprised of N-C, C-O and S-C combinations
(Figure 5). Since all analogs prepared had IC50s >25M, we
speculated that the sulfonamide linker may be optimal by virtue
of its scaffolding effect or due to specific contacts made between
the O- or N-atom with Mcl-1 protein residues.
The SAR trends from exploratory libraries allowed us to
propose a tentative binding hypothesis. We speculated that the
hydrophobic 2-Cl-5-CF3-phenyl ring on the left-hand side of the
molecule occupied a sterically confined hydrophobic pocket in
the BH3 binding region of Mcl-1. The lipophilic pockets in Mcl-
1, designated as P1-P4 (Figure 7a) may be suitable places for
such a group since small hydrophobic residues from the Bim
peptide alpha helix: ILE 86, LEU 90, VAL 93 and MET 97 each
occupy the respective P1-P4 pockets based on Mcl-1/Bim co-
crystals.26-29 Analogous pockets (P2 and P4) in Bcl-2 have been
targeted as “hot spots” in small molecule drug design using an
SAR by NMR fragment based screening approach.30 The 2,5-
dichlorophenyl ring on the opposite side of the molecule may
project away from the lipophilic pocket, toward another region of
the BH3 binding helical domain. The observation that
substitution on the edge of the right-hand side leads to flat SAR
suggested that extending functional groups from the meta or para
positions of the RHS ring may enable productive interactions
with other residues in the BH3 binding domain. The thiophene
scaffold present in 20 was therefore selected as a core template to
test our hypothesis.
Incorporating larger, hydrophobic groups on the right-hand side
of the molecule generally resulted in equipotent compounds.
Exceptions to this occurred with the phenethyl derivatives. Key
examples from this subseries included the first sub-micromolar
inhibitor 37, and structurally related chiral phenethanol
compounds 38 and 43.

Cl
Table 3. SAR of 4-methyl thiophene derivatives
Cl
O
S
H
N
O
4
Cl
F3C IC50 = 3.1 M
Cl
CF3
CF3
Cl
CF3
CF3
Cl
Cl
Cl
Cl
Cl
O
S
HN
S
S
N
H
O
O
Cl
Cl
O
Cl
Cl
27
28
29
30
Cl
Cl
CF3
CF3
CF3
Cl
Cl
Cl
H
N
O
O
Cl
Cl
Cl
Cl
Cl
31
32
33
Figure 5. Modifications of the sulfonamide linker; deviations at the linker
portion represented here lead to inactive compounds all showing IC50’s > 25
M
Previously reported structures of Mcl-1 show Arg residues
such as Arg263 in close proximity to the hydrophobic pockets of
the BH3 domain.31 As part of our design strategy to introduce
electrostatic interactions with the Arg residue, a carboxylic acid
functionality was introduced on the right-hand side of the
molecule. While many analogues from this design hypothesis
failed to show improvements in potency, the phenylalanine
derivative 40 displayed a 6-fold improvement in potency from
the original hit 20. Separation of the racemic mixture revealed
that the R enantiomer preferentially binds to the target with an
approximate 4-fold difference in IC50. As a follow-up to 40,
further analogues were prepared to understand the role of the
charged group and the phenyl ring. Simply removing the benzyl
group (41 vs. 56) resulted in a ~3-fold loss in activity while
extending the carboxylic acid chain by an atom length (44)
resulted in an additional ~7-fold loss (56 vs. 44). Changes to the
benzyl ring resulted in modest changes to the activity as shown in
Table 4 with the following relative potencies: benzyl (41) > iPr
(48) = CH2CH2Ph (52) > Me (47). Incorporating heteroatoms into
the benzene ring also had a modest effect on reducing the activity
shown by tryptophan derivative 53 and 3-pyridyl derivative 55.
More polar rings such as pyrrazole 50 were ~9-10 fold less
potent.
Replacing the carboxylic acid with other ionizable groups
resulted in comparable activities. Tetrazoles 59 and 60 had
similar IC50s vs. the corresponding carboxylic acid analogues.
The acylsulfonamide derivatives 61 and 62 were slightly better
and represented the most potent compounds in the series with
IC50s of 53 nM and 73 nM respectively. Expansion from this set
however revealed that the negative charge was not essential for
activity as shown by the ester and amide adducts 64 and 65
which were comparable in potency to their acid-containing
counterparts.

Table 4. SAR of 4-methyl thiophene derivatives
(Figure 8). The amide carbonyl oxygen lies within hydrogen
bonding distance of His224 (3-3.5 Å). The benzyl ring on the
right-hand side is loosely associated with the floor of the P4
pocket, which is shallow, hydrophobic and otherwise devoid of
features that could be targeted in order to optimize interactions
with small molecule inhibitors. The 2-Cl and 5-CF3 groups
project deep into hydrophobic regions of the P2 pocket, with an
orthogonal orientation relative to the bound BH3 peptide helix.
The 2,5-disubstituted phenyl ring creates a unique pocket, absent
in the BH3 bound Mcl-1 structure, highlighting the plasticity of
the P2 pocket of Mcl-1. The sulfonamide oxygen lies 3.46 Å
from the N-atom of Arg263. The –NH bond of the sulfonamide
is
extensively
Figure 6. SPR sensorgram of 43
Biophysical characterization by surface plasmon resonance was
performed with 43 at several concentrations with biotinylated
Mcl-1. Carbonic anhydrase II was used as a control protein for
measuring binding selectivity. The KD determined by SPR (165
nM) was consistent with the IC50 measured by fluorescence
polarization (149 nM). Together, SPR data indicated that
representative compound, 43, showed selective and saturable
binding consistent with a well behaved Mcl-1 inhibitor (Figure 6;
additional material available in supplementary information).
A co-crystal structure of 65 with Mcl-1 revealed key insights
into the critical ligand-protein interactions present in the series

O
Cl
Cl
O
S
Cl
Cl
H
Cl
S
O
Cl
Cl
R
H
O
S
NH2
N
N
R
ClO2S
R
NH2
R
O
O
Pyridine, DCM
Pyridine, DCM
CF3
Cl
15-26
CF3
4-14
Cl
Cl
CF3
O
H
Cl
Cl
CF3
NaBH4,
AcOH, DCE
Cl
DCE, 5% AcOH, 80 o
C
H2N
Cl
+
+
N
H
O
+
91%
N
H
30
NH2
1h;dioxane-DME, NaBH4
80%
Cl
Cl
CF3
Cl
Cl
Cl
31
Cl
Cl
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
mCPBA
Cl
Cl
DMF, Cs2CO3,
50 oC, 46%
SH
TEA, DMF
O
S
OH
Br
O
Br
+
S
77%
O
Cl
Cl
29
28
32
CF3
CF3
Cl
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
O
O
S
HO
Cl
Cl
Cl
K2CO3, DMF
83%
O O
S
Br
+
H2N
pyridine
Cl
O
+
N
H
58%
Cl
33
Cl
CF3
Cl
27
CF3
Cl
CF3
Scheme 1. Synthesis of exploratory chemistry targets
O
Cl S
O
OMe
S
Cl
H2N
R
O
Cl
O
S
Cl
O
H
H
NH2
1. Pyridine, DCM
N
BOP, TEA, DMF
N
S
H
N
R
OH
S
S
O
O
2. NaOH, THF-
MeOH-H2O
2-18 h
O
O
CF3
Cl
CF3
34-39, 43, 53
CF3
O
Cl
O
Cl
O
H
H
H
N
S
BOP, TEA, DMF, 23 oC,
O
N
S
H
N
S
NaOH, MeOH-H2O-
THF, 23 oC, 2-18 h
H
N
H
N
S
N
O
S
S
O
O
OH
O
R
n
N
n
2-18 h, RNH2
O
O
H
R
O
O
R
n = 0,1
R
O
40-42, 44-57,
I-61 to I-64
CF3
CF3
CF3
I-40 to I-42, I-44
to I-57, 65
n = 0,1
63, 64
O
Cl
H2N
S
R
O
H
O
N
O
S
H
O
O
N
S
O
S
N
EDC, DMAP
R
H
O
R
CF3
61, 62
Cl
Cl
O
S
O
H
H
N
NH
N
N
N
N
S
H
H
N
N
S
S
CN
O
O
O
O
R
R
CF3
CF3
59, 60
I-59, I-60
Scheme 2. Synthetic routes to targets spanning P2 to P4.
Table 5. Physico-chemical properties of select Mcl-1 inhibitors.
O
H
Cl
S
N
R
S
O
O
CF3
ID
MW
clog D pH 7.4
LiPE
MLM
61
686
5.0
2.3
81
62
41
546
1.7
5.1
95
53
624
2.8
4.3
91
586
1.8
5.1
94
HLM
74
99
66
98

PAMPA
Solubility (M)
0.24
--
0.14
--
--
100
0.12
100
*PAMPA permeability values expressed as the mean log Papp in cm/sec; lipE = pIC50 – log P; MLM = mouse liver microsomes assay
values expressed as a percentage of parent compound left after 30 min.
Leu 62
Ile 65
Phe 69
Ile 58
P1
P2
P3
P4
Figure 7. (a) Overview of BH3 alpha helix bound to Mcl-1 (b) Conserved residues of BH3 Bim protein interact with P1-P4 region of
Mcl-1’s binding domain (2NL9). Residues of the key hydrophobic protein-protein interactions between the BH3 alpha helix and
corresponding P1- P4 pockets of Mcl-1.
P3
P4
P2
Figure 8. (a) X-Ray crystal structure of 65 and Mcl-1 showing the key H-bonding interactions; (b) bound structure (65) depicting the
degree of plasticity in the P2 binding site (PDB code 6P3P).
general, the highly lipophilic components required for binding
combined with the ionized, acidic residue provide a balance of
physicochemical properties maintaining the clogD value within
drug-like space. The most potent analogue, 61, has a high clogD
of 5 and therefore much lower lipE values when compared to 41
or 53 (lipEs of 2.3 vs. 5). Since the affinity of 41 and 53 is
derived to a greater degree from specific interactions with the
target, they were considered to provide a better starting point for
lead optimization efforts.
The lack of prominent binding features in P4 created a challenge
to attaining additional binding affinity.36,6 Indeed, none of our
medicinal chemistry design efforts succeeded in capturing
additional interactions in P4. While the orientation of the
thiophene core provided ample opportunities to probe the region,
ionized under the buffered conditions of the biochemical assay,
which we speculated may enhance a potential electrostatic
interaction with Arg263. Perhaps more important is the bond
angle of the sulfonamide, where, unlike the simple 2-atom linkers
in 27-33, maintains an optimal 90° bend to allow the 2- chloro-5-
CF3 phenyl group to project into the deepest part of the P2 pocket
while keeping the methyl thiophene ring close to the ridge
between the P2 and P3 sites. The structural changes at P2
highlight the extent of flexibility inherent in this target. Reported
small molecule Mcl-1 co-crystal structures32-35 also show high
degrees of plasticity in the region of the P2 pocket.
Table 5 shows the series possesses favorable solubility and
microsomal stability in human and mouse microsomes. In

derivatives of the phenethyl group including para and meta
phenyl ring substituents, branching substitution at the carbon
atoms alpha and beta to the amide nitrogen, as well as extending
the length of the linker region all proved unsuccessful in gaining
additional ligand/protein interactions to enhance biochemical
potency. Little insight can be gained from X-ray structures in this
regard as the aromatic rings lie perpendicular to the floor of the
relatively flat and featureless P4 pocket. The benzyl ring of 65
lies in a strikingly similar position as the BH3 peptide residue
Phe69 in the Bim bound Mcl-1 complex (Figure 7a-b). BH3
proteins Nova, Bax, and Bak all bind tightly to Mcl-1 in a
binding groove spanning ~10 Å. An efficacious Mcl-1 inhibitor,
therefore, will likely need extraordinary binding affinity to
effectively compete with the BH3 binding proteins in vivo. The
clinical candidates ABT199 and ABT263 engage multiple
pockets of Bcl-2 spanning P2-P4 and similar design approaches
may also be required to produce effective Mcl-1 candidates.
Inhibitors reported by Abbvie occupy P2-P4 and maintain an
ionic charge interaction between the ligand’s carboxylic acid and
Arg263. Amgen recently reported successfully designing potent
and drug-like Mcl-1 inhibitors by restricting the conformational
degrees of freedom using structure-based drug design. The
macrocycle AMG-176 maintained a rigid, bioactive conformer
with desirable potency profiles against Mcl-1 dependent cell
lines.14
Mcl-1, myeloid cell leukemia; Bcl-2, B-cell lymphoma 2.
More extensive design approaches targeting the P4 pocket or
addition of specific groups that target the Arg263 residue will
inevitably be needed to drive potency in this series of inhibitors.
In summary, the discovery of Biaryl sulfonamide Mcl-1
inhibitors is described. Traditional medicinal chemistry efforts
aided by X-Ray crystallography successfully advanced an HTS
hit to a more lead-like, potent inhibitor of the Mcl-1/Bid
complex. The lessons learned here underscore some of the key
challenges in designing small molecule inhibitors of protein-
protein interactions.
ASSOCIATED CONTENT
Supporting Information. Analytical methods, materials,
instrumentation, general materials for the synthesis of
compounds 41, 61, 62, and 63, protein production and structure
determination, data collection and refinement statistics, Mcl-1-
tBid pulldown assay, biophysical characterization with surface
plasmon resonance. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: followsb@gmail.com.
Notes
The authors Ann-Marie Campbell, Shawn Fessler, Hongbin Li,
Bruce Follows, Deepali Gotur, Zhongguo Wang, Xiaozhang
Zheng, Lisa Molz, Cokey Nguyen, Torsten Herbertz, Liann
Wang, Timm Baumeister, Kenneth Bair and Mary Margaret
Zablocki were employees at Forma Therapeutics during the time
of the research was conducted.
ACKNOWLEDGMENT
The authors thank Peter Ettmayer, Klaus Rumpel and Jim
Kyranos for coordinating the studies with Biosensor tools,
David Myszka for conducting SPR experiments, Angela Toms
for providing graphics depicting ligands bound to the crystal
structure of Mcl-1, Kenneth Barr and Chris Dinsmore for
reviewing the manuscript.
ABBREVIATIONS

REFERENCES
AND
NOTES
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