Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor

Article abstract of DOI:10.1021/acsmedchemlett.1c00063

Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF inhibitors reported to date.

Full text of DOI:10.1021/acsmedchemlett.1c00063

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Letter
Targeting KRAS Mutant Cancers via Combination Treatment:
Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor
Malcolm P. Huestis, Matthew R. Durk, Charles Eigenbrot, Paul Gibbons, Thomas L. Hunsaker, Hank La,
Dennis H. Leung, Wendy Liu, Shiva Malek, Mark Merchant, John G. Moffat, Christine S. Muli,
Christine J. Orr, Brendan T. Parr, Frances Shanahan, Christopher J. Sneeringer, Weiru Wang, Ivana Yen,
Jianping Yin, Joachim Rudolph,* and Michael Siu*
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ABSTRACT: Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF
inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge
contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The
improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation
of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an
HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF
inhibitors reported to date.
KEYWORDS: RAF, pan-RAF, kinase inhibitor, cobimetinib, MAPK, KRAS mutant cancer
effector of particular importance is RAF (consisting of the
three isoforms ARAF, BRAF, and CRAF), the downstream
kinase member of the MAPK pathway. RAF interaction with
GTP-bound RAS drives RAF dimerization and phosphor-
ylation, and activated RAF in turn phosphorylates its substrate
MEK1/2 to transmit signaling within the MAPK pathway.
Until recently,2 direct therapeutic targeting of RAS has
proven challenging; therefore, targeting of inherently more
druggable downstream kinases in the MAPK pathway has been
of considerable interest over the last decades. However, these
efforts have met significant obstacles, in part due to the
AS mutations are found in nearly 20% of all cancers, but
Rdespite their prevalence and considerable research efforts
Figure 1. GNE-0749, a potent and selective Type II pan-RAF
inhibitor.
Received: January 27, 2021
Accepted: March 31, 2021
Published: April 21, 2021
over the past three decades no effective therapeutic has been
approved to date.1 Mutations of RAS are characterized by an
enrichment of its active GTP-bound population, leading to
uncontrolled downstream signaling to effector proteins. An
https://doi.org/10.1021/acsmedchemlett.1c00063
© 2021 American Chemical Society
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Table 1. Evaluation of Hinge Binder Motifs
a
Table 2. Discovery of Pan-RAF Inhibitor GNE-9815 (7)
a
MDCK apical → basolateral Papp (apparent permeability, ×10−6 cm s−1); efflux = BA/AB; LM = liver microsome CLhep human/rat/mouse.
propensity of RAF inhibitors to paradoxically activate the
pathway3 as a result of detrimental negative feedback loops
integral to the MAPK pathway.4 In our efforts to overcome
these obstacles, we recently reported on the synergistic use of
Type II RAF inhibitors in combination with MEK inhibitors to
target KRAS mutant cancers.5 The binding mode of Type II
RAF inhibitors obliterates the formation of asymmetric RAF
dimers thus thwarting undesirable pathway activation.
Conversely, the combination with MEK inhibitors disables
negative feedback loops, thereby sensitizing tumors to RAF
inhibitors.
We recently reported the discovery of a potent and selective
Type II RAF inhibitor, GNE-0749, which showed significant
antitumor efficacy in combination with the MEK inhibitor
cobimetinib in a HCT116 xenograft tumor model (Figure 1).6
Concurrent with this effort, we also investigated novel hinge
binder moieties with improved physicochemical properties.
Specifically, we sought to modify the 2-aminopyrido[2,3-
d]pyrimidine hinge binder of LY30091207 (1) with the goal of
reducing hydrogen bond donors and rotatable bonds to
support oral dosing (Table 1). Antiproliferative activity was
compared in BRAF mutant A375 and KRAS mutant A549 cells
along with A549 in the presence of a submaximal
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Figure 2. Kinome tree for 7, tested against 226 kinases at a concentration of 0.1 μM.
concentration (100 nM) of cobimetinib. Significant A549
potency shift in the presence versus absence of cobimetinib
cotreatment is indicative of synergistic inhibition.
Beginning with pyrido[2,3-d]pyrimidinone 2, a compound
with a hinge binder motif that maintains the same kinase hinge
hydrogen bond donor/acceptor as LY3009120 (1), compara-
ble potency was achieved, albeit with poor kinase selectivity
(15/26 kinases with >70% inhibition at 0.1 μM vs 11/29 for
1), which may be contributing to the antiproliferative activity.
Possessing a more lipophilic 3-aminoisoquinoline heteroarene,
compound 3 partially restored kinase selectivity with an
increase in biochemical potency. To further improve kinase
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nontraditional polarized N-methyl C−H interaction with
Cys532 CO (3.1 Å).8 With less discrete polarized hinge
contacts, the exquisite selectivity for RAF kinases may be due
to van der Waals π-stacking interactions of the heteroaryl hinge
binder with Trp531 (unique to ARAF, BRAF, and CRAF),
Phe595 (DFG), and Phe583 interactions. The pyrido nitrogen
faces the bulk solvent channel and makes little direct contact
with the protein; therefore, it is not obvious how the nitrogen
imparts such a dramatic increase in selectivity.
Based on these promising in vitro results, phthalazinone 4
and pyridopyridazinone 7 were progressed to in vivo studies.
Pharmacokinetic (PK) data from these compounds in mice are
shown in Table 3. Both compounds showed low blood
clearance, moderate volume of distribution, and short half-life.
However, 7 offered significantly better oral bioavailability upon
dosing as a crystalline suspension using a methylcellulose/
Tween (MCT) formulation.
Given the optimal combination of cellular potency and
pharmacokinetic properties, 7 was progressed to further
studies. To confirm that the RAF inhibition elicited by 7
combined with MEK inhibition was synergistic in KRAS
mutant tumors, we performed pharmacokinetic/pharmacody-
namics (PKPD) studies to assess the combination of 7 with
cobimetinib. Single-agent treatment with 7 resulted in pathway
inhibition as demonstrated by partial inhibition of pRSK
between 2 and 24 h, but more robust, albeit transient,
inhibition of the downstream MAPK target genes, DUSP6 and
SPRY4 (Figure 4). In contrast, cobimetinib alone showed
minimal reduction in pRSK at any time point, with modest
reduction in downstream expression of the MAPK target
genes, DUSP6 and SPRY4. The combination of 7 and
cobimetinib afforded increased inhibition of pRSK at 2 and
8 h with rebound at 24 h. The increased pathway inhibition by
the combination of 7 and cobimetinib resulted in deeper
inhibition of the downstream MAPK target genes DUSP6 and
SPRY4 with maximal inhibition observed at 8 h and with a
more modest rebound in levels at 24 h, post final dose. This
data corroborates earlier findings6 that the combination of
RAF and MEK inhibition results in increased MAPK pathway
suppression in a KRAS mutant tumor setting. The pristine
kinase selectivity observed for compound 7 provides further
confidence that the observed synergistic effect with the MEK
inhibitor cobimetinib is driven exquisitely by RAF inhibition.
In summary, we have reported here the discovery of pan-
RAF inhibitors that avoid paradoxical activation based on a
type II kinase binding mode. Limiting the hinge interactions to
improve kinome selectivity led to the discovery of compounds
with novel 1-(2H)-phthalazinone and pyrido[2,3-d]pyridazin-
8(7H)-one kinase hinge-binding motifs. GNE-9815 (7) is a
potent pan-RAF inhibitor showing synergistic activity in KRAS
mutant A549 and HCT116 cancer cells in combination with
the MEK inhibitor cobimetinib. The synergistic pharmacody-
namic effects were also demonstrated in HCT116 tumor-
bearing mice. The kinase selectivity imparted by the pyrido-
[2,3-d]pyridazin-8(7H)-one ring system makes GNE-9815 (7)
one of the most kinase selective RAF inhibitors reported to
date. Based on its favorable property profile, including
exquisite kinase selectivity, satisfactory solubility, and rodent
oral exposure, we believe that GNE-9815 could become a
valuable chemical probe for researchers interested in inter-
rogating RAF biology.
Figure 3. X-ray crystal structure of 7 bound in a mutant BRAF
construct (PDB ID 6XLO).
Table 3. Property Evaluation of Compounds 4 and 7
a
a
compd
mouse CLb
Vdss
,
t1/2
F
b
4
7
22 mL min−1 kg−1
17 mL min−1 kg−1
2.1 L kg−1, 1.3 h
1.7 L kg−1, 1.9 h
2% (MCT)
b
37% (MCT)
a
b
IV 1 mg kg−1 10% DMSO, 10% Cremophor EL in saline. PO 5 mg
kg−1.
selectivity, we aimed to minimize the common hinge
interactions of 3 and sought to replace the aminoisoquinoline
N−H with a polarized C−H, leading to the design of 1-(2H)-
phthalazinone 4.8 To the best of our knowledge, this is the first
example of the use of this heteroarene as a hinge-binding motif
in kinase inhibitors. Gratifyingly, phthalazinone 4 exhibited
similar biochemical potency to 3, but along with improved
kinase selectivity (5/29 kinases with >70% inhibition at 0.1
μM).
Aiming to increase RAF potency in this new series and
reduce the number of polar N−H groups, we investigated
whether a suitable alternative to the urea moiety could be
found (Table 2). Deletion of one of the nitrogen atoms from
the urea portion of the molecule afforded benzamide 5 which
maintained the biochemical potency of phthalazinone 4 but
displayed poor cellular potency (∼6-fold loss). Changing the
benzamide to an aryl anilide functional group similar to other
type II RAF inhibitors,9 RAF kinase cellular potency was
restored, while simultaneously lowering log D (compound 6).
However, the overall physicochemical properties and micro-
somal stability were not improved. Finally, we discovered that
the introduction of an additional nitrogen atom to the 1-(2H)-
phthalazinone ring in compound 6, to provide pyrido[2,3-
d]pyridazin-8(7H)-one 7 (GNE-9815), reduced lipophilicity,
improved microsomal stability, and imparted a dramatic
increase in kinase selectivity such that a panel of 223 kinases
found no inhibition > 70% at a concentration of 0.1 μM
(besides RAF kinases, Figure 2).10
An X-ray crystal structure of 7 bound in a mutant BRAF
construct (see SI Methods) is shown in Figure 3. As expected,
the substituted benzamide occupies the lipophilic back pocket
of RAF, while the pyrido[2,3-d]pyridazin-8(7H)-one ring
system shows interaction with the backbone N−H (3.1 Å)
of Cys532 at the hinge of the protein in addition to a
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Figure 4. PKPD study for GNE-9815 (7) in HCT116 xenograft mice.
orcid.org/0000-0002-2822-6584; Phone: 650-467-7764;
Email: siu.michael@gene.com
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00063.
Authors
Malcolm P. Huestis − Discovery Chemistry, Genentech, Inc.,
South San Francisco, California 94080, United States;
orcid.org/0000-0002-6038-3838
Matthew R. Durk − Drug Metabolism and Pharmacokinetics,
Genentech, Inc., South San Francisco, California 94080,
United States
Experimental procedures, compound characterization,
NMR and HPLC spectra for compound 7, detailed
kinase selectivity panel data for compounds 2−7,
crystallographic statistics for protein cocrystal structure
of 7 (PDF)
Charles Eigenbrot − Structural Biology, Genentech, Inc.,
South San Francisco, California 94080, United States
Paul Gibbons − Discovery Chemistry, Genentech, Inc., South
San Francisco, California 94080, United States
Thomas L. Hunsaker − Translational Oncology, Genentech,
Inc., South San Francisco, California 94080, United States
Hank La − Drug Metabolism and Pharmacokinetics,
Genentech, Inc., South San Francisco, California 94080,
United States
AUTHOR INFORMATION
■
Corresponding Authors
Joachim Rudolph − Discovery Chemistry, Genentech, Inc.,
South San Francisco, California 94080, United States;
Phone: 650-467-8867; Email: rudolph.joachim@gene.com
Michael Siu − Discovery Chemistry, Genentech, Inc., South
San Francisco, California 94080, United States;
795
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Dennis H. Leung − Small Molecule Pharmaceutical Sciences,
Genentech, Inc., South San Francisco, California 94080,
United States
(oral); RAF, rapidly accelerated fibrosarcoma; SPRY4, sprouty
RTK signaling antagonist 4; TPSA, topological polar surface
area; Vdss, volume of distribution
Wendy Liu − Discovery Chemistry, Genentech, Inc., South San
Francisco, California 94080, United States
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■
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John G. Moffat − Biochemical and Cellular Pharmacology,
Genentech, Inc., South San Francisco, California 94080,
United States
Christine S. Muli − Small Molecule Pharmaceutical Sciences,
Genentech, Inc., South San Francisco, California 94080,
United States
Christine J. Orr − Translational Oncology, Genentech, Inc.,
South San Francisco, California 94080, United States
Brendan T. Parr − Discovery Chemistry, Genentech, Inc.,
South San Francisco, California 94080, United States
Frances Shanahan − Molecular Oncology, Genentech, Inc.,
South San Francisco, California 94080, United States
Christopher J. Sneeringer − Biochemical and Cellular
Pharmacology, Genentech, Inc., South San Francisco,
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00063
Notes
(7) (a) Henry, J. R.; Kaufman, M. D.; Peng, S.-B.; Ahn, Y. M.;
Caldwell, T. M.; Vogeti, L.; Telikepalli, H.; Lu, W.-P.; Hood, M. M.;
Rutkoski, T. J.; Smith, B. D.; Vogeti, S.; Miller, D.; Wise, S. C.; Chun,
L.; Zhang, X.; Zhang, Y.; Kays, L.; Hipskind, P. A.; Wrobleski, A. D.;
Lobb, K. L.; Clay, J. M.; Cohen, J. D.; Walgren, J. L.; McCann, D.;
Patel, P.; Clawson, D. K.; Guo, S.; Manglicmot, D.; Groshong, C.;
Logan, C.; Starling, J. J.; Flynn, D. L. Discovery of 1-(3,3-
Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)-
pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF
Inhibitor With Minimal Paradoxical Activation and Activity Against
BRAF or RAS Mutant Tumor Cells. J. Med. Chem. 2015, 58, 4165−
4179. (b) Peng, S.-B.; Henry, J. R.; Kaufman, M. D.; Lu, W.-P.; Smith,
B. D.; Vogeti, S.; Rutkoski, T. J.; Wise, S.; Chun, L.; Zhang, Y.; Van
Horn, R. D.; Yin, T.; Zhang, X.; Yadav, V.; Chen, S.-H.; Gong, X.; Ma,
X.; Webster, Y.; Buchanan, S.; Mochalkin, I.; Huber, L.; Kays, L.;
Donoho, G. P.; Walgren, J.; McCann, D.; Patel, P.; Conti, I.;
Plowman, G. D.; Starling, J. J.; Flynn, D. L. Inhibition of RAF
Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor
Activities in RAS or BRAF Mutant Cancers. Cancer Cell 2015, 28,
384−398. (c) Chen, S.-H.; Gong, X.; Zhang, Y.; Van Horn, R. D.; Yin,
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Bhagwat, S. V.; Beckmann, R. P.; Tiu, R. V.; Buchanan, S. G.; Peng,
S.-B. RAF Inhibitor LY3009120 Sensitizes RAS or BRAF Mutant
Cancer to CDK4/6 inhibition by Abemaciclib via Superior Inhibition
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The authors declare the following competing financial
interest(s): All authors are employees/former employees of
Genentech, Inc. and may hold stock in Roche Holding AG. All
studies were funded by Genentech, Inc.
Coordinates and structure factors for the BRAF domain
complex are available in the PDB with accession code 6XLO
(7). The authors will release the atomic coordinates and
experimental data upon article publication.
ACKNOWLEDGMENTS
■
M.P.H. thanks Kim Huard for support and encouragement.
Kinase selectivity data courtesy of Selectscreen service from
Life Technologies, a Thermo Fisher company, Madison, WI,
USA. We thank staff of Beamline 5.0.2 of the Advanced Light
Source for assistance during data collection.
ABBREVIATIONS USED
■
CL, clearance; DELFIA, dissociation-enhanced lanthanide
fluorescence immunoassay; DFG, Asp-Phe-Gly; DUSP6, dual
specificity phosphatase 6 kinase; ERK, extracellular signal-
regulated kinase; F, bioavailability; HCT, human colorectal
cancer cells; IV, intravenous; KRAS, Kirsten rat sarcoma;
log D, log of distribution coefficient; MDCK, Madin−Darby
canine kidney cell; MEK, mitogen-activated protein kinase
kinase; MAPK, mitogen-activated protein kinase; MCT,
methylcellulose-tween; MP, melting point; MS, mass spec-
trometry; Papp, permeability coefficient; PK, pharmacokinetic;
PKPD, pharmacokinetic/pharmacodynamics; PO, per os
(8) Example of N-methyl polarized CH protein interactions: Hanan,
E. J.; van Abbema, A.; Barrett, K.; Blair, W. S.; Blaney, J.; Chang, C.;
Eigenbrot, C.; Flynn, S.; Gibbons, P.; Hurley, C. A.; Kenny, J. R.;
Kulagowski, J.; Lee, L.; Magnuson, S. M.; Morris, C.; Murray, J.;
Pastor, R. M.; Rawson, T.; Siu, M.; Ultsch, M.; Zhou, A.; Sampath,
D.; Lyssikatos, J. P. Discovery of Potent and Selective Pyrazolopyr-
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