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. 2020 Dec 14;12(1):30–38. doi: 10.1021/acsmedchemlett.0c00338

Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor

Brian J Groendyke †,‡, Behnam Nabet †,‡, Mikaela L Mohardt †, Haisheng Zhang §,∥, Ke Peng ∥, Eriko Koide †, Calvin R Coffey †, Jianwei Che †,‡, David A Scott †,‡, Adam J Bass ∥,⊥, Nathanael S Gray †,‡,*
PMCID: PMC7812608  PMID: 33488961

Abstract

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Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure–activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline “tail,” which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC50 = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.

Keywords: FAK, selective inhibitors, structure−activity relationships, aminothiazole, anticancer agents

Focal adhesion kinase (FAK, also known as protein tyrosine kinase 2 [PTK2]) is a tyrosine kinase with important roles in reorganizing actin and focal adhesions, coordinating PI3K-AKT and integrin signaling networks, and regulating nuclear gene expression programs. In the context of cancer, FAK plays prominent kinase-dependent and kinase-independent roles in coordinating migration, angiogenesis, and anchorage-independent cell survival.1 FAK is commonly overexpressed or amplified in many cancers, including ovarian, breast, colorectal, and pancreatic cancers. We recently demonstrated that FAK coordinates YAP/TAZ, PI3K-AKT, and β-catenin signaling in diffuse gastric cancer.2 For these reasons, targeted disruption of FAK has been of great interest and a number of potent FAK inhibitors have been developed and advanced to clinical trials. While FAK inhibition has been tolerable and leads to cytostatic effects, single-agent clinical efficacy of FAK inhibitors is limited.3 Combination approaches with FAK inhibitors are under active investigation. For example, FAK inhibitors have been shown to sensitize pancreatic cancer to chemotherapy or checkpoint inhibitors,4 leading to several ongoing clinical trials.5

Many of the existing FAK inhibitors, such as defactinib (VS-6063),6 VS-4718 (PND-1186),7 PF-573228,8 CEP-37440,9 and TAE226,10 share a 2,4-diaminopyrimidine or 2,4-diaminopyridine motif (Figure 1). These compounds are highly potent ATP-competitive kinase inhibitors, with biochemical IC50 values in the single-digit nanomolar range but display either dual kinase inhibition or significant activity against other kinases. Several bicyclic scaffolds, namely, 7-azaindoles,11 pyrrolopyrimidines,12 and imidazotriazines,13 have delivered potent (IC50 < 50 nM) FAK inhibitors, but the full kinome profiles of these series are not reported. Although off-target activity is at times therapeutically advantageous,14,15 off-target effects from nonselective probes can confound chemical-biology studies. In this study, we describe the identification and characterization of a highly selective FAK inhibitor, BJG-03-025. BJG-03-025 is based on a privileged benzopyrimidodiazepinone core scaffold which we have elaborated previously to target kinases including: ERK5,16 PI3Kδ,17 TNK2,18 and nonkinases such as BRD4.19 BJG-03-025 was identified following a systematic structure–activity relationship campaign after observing serendipitous selectivity for this scaffold class from kinome-wide profiling studies. We observe that BJG-03-025 displays antiproliferative activity in three-dimensional (3D)-breast and gastric cancer models and impacts cellular signaling and migration. Our selective FAK inhibitor is a valuable probe for evaluation of FAK-specific biology.

Figure 1.

Figure 1

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Existing FAK inhibitors are potent but display multikinase activity.

Previous work in our group has shown the tricyclic benzopyrimidodiazepinone core to be a privileged scaffold for the design of potent and selective kinase inhibitors. During a campaign to replace the benzene of the benzopyrimidodiazepinone core with heteroaryl rings, KINOMEscan profiling revealed 1 (BJG-01-181) as an exceptionally selective FAK inhibitor, displaying >65% inhibition of only 5 out of 402 kinases at a testing concentration of 10 μM (Figures 2 and S1, Table S1). A biochemical kinase assay confirmed 1 as a moderately potent FAK inhibitor (IC50 = 62.2 nM); although less potent than other FAK inhibitors, 1 is notably more selective (Table S2). From this starting point, we explored the structure–activity relationships (SAR) of this novel scaffold to improve FAK potency and better understand the source of its kinome selectivity.

Figure 2.

Figure 2

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Identification of 1 (BJG-01-181), a highly selective FAK inhibitor and chemical structures of related analogues.

A comparison of 1 with a structurally similar thiazole isomer (2, FAK IC50 > 10 000 nM) revealed that the thiazole nitrogen must be in the “top” position, adjacent to the diazepinone carbonyl (Figure 2). We surmised that this nitrogen may provide an important hydrogen-bonding interaction. The closely related pyrazole 3 displayed similar FAK potency (IC50 = 132 nM), lending further support to this hypothesis. For other members of the pyrimidodiazepinone series, amide N-methylation often leads to increased potency due to a beneficial interaction with the gatekeeper residue.20,21 Furthermore, the N-methylated compounds generally possess better pharmacokinetic (PK) properties than the secondary amides.18 Compound 4 (BJG-03-025), an N-methyl matched-pair with 1, was synthesized and showed a 3-fold improvement, with a FAK IC50 of 20.2 ± 1.9 nM. Further optimization focused on the N-methylated tricyclic core. SAR studies to investigate the effects of different aniline “tails” and substitution at the tricyclic core were conducted in parallel (Table 1). To enable direct comparisons, aniline screening was conducted using the 2-methyl thiazole core 10. Similarly, to interrogate the effects of substitution patterns on the tricyclic core, the 2-methoxy-4-(4-(4-methylpiperazinyl)piperidinyl) aniline was used in all examples.

Table 1. Structure–Activity Relationships of the Aniline Component.

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a

IC50 measured using the Z’LYTE assay (ThermoFisher Scientific), as duplicate experiments.

b

IC50 of viability of MDA-MB-231 cells in ultra-low adherent 3D-spheroid suspensions. Values are derived from data presented in Figures 5B and S8 and are representative of n = 3 independent experiments. N.D., not determined.

c

n = 4, two independent batches each tested in duplicate.

Tricyclic core 10 can be obtained via the synthetic scheme shown in Scheme 1. Other analogues were prepared using the same synthetic sequence, or with slight modifications (see the Supporting Information (SI) for details). Commercially available ethyl 2-methylthiazole-4-carboxylate 5 was brominated with N-bromosuccinimide (NBS) to afford bromothiazole 6. Palladium-catalyzed amination with benzophenone imine, followed by hydrolysis provided primary amine 7 in good yield. Deprotonation of the primary amine and treatment with iodomethane provided N-methyl 8. All attempts to forge the thiazole C5–N bond via nitration of 5 or SNAr reaction of 6 were unsuccessful. N-Arylation of 8 with 2,4-dichloro-5-nitropyrimidine under NaH conditions provided intermediate 9, which was subjected to an iron-promoted reductive cyclization and subsequent methylation with iodomethane to provide the tricyclic core 10. The final compounds were prepared by Buchwald–Hartwig amination with the corresponding aniline or heterocyclic amine.

Scheme 1. Synthesis of 4 and 11–28.

Scheme 1

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Reagents and conditions: (a) NBS, acetonitrile, 40 °C, 61%. (b) (i) Pd2 (dba)3, BINAP, Cs2CO3, benzophenone imine, toluene, 80 °C, (ii) THF/1 M aq HCl (4:1 mixture), rt, 68% over two steps. (c) NaH, MeI, THF, 0 °C to rt, 41%. (d) NaH, 2,4-dichloro-5-nitropyrimidine, THF, 0 °C to rt, 59%. (e) Fe, glacial acetic acid, 50 °C. (f) NaH, MeI, DMF, 0 °C to rt, 48% over two steps. (g) Pd2 (dba)3, XPhos, K2CO3, amine, t-BuOH 100 °C.

Modification of the solvent-exposed side chain aimed to improve the potency of 4 while maintaining high kinome selectivity. We targeted several key residues in the solvent-exposed channel, including Arg426, Gln438, and Glu506 (Figure 3), by incorporating hydrogen-bond donors or acceptors into the aniline tail. A variety of modifications yielded inhibitors with biochemical IC50s in the 30–60 nM range (Table 1), but did not improve upon the potency of 4. In contrast, several side chains, such as hydroxyethyl ether 19, tetrahydroquinolinone 22, and pyrazole 27, were not tolerated and resulted in lower biochemical potency.

Figure 3.

Figure 3

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Docking of 4 with FAK (PDB 6I8Z). (A) Key interactions of 4 with active-site residues, notably the critical hydrogen-bond of the thiazole nitrogen with Asp564. (B) FAK surface map shows the U-shaped active site, with the 2-methyl group extending into a hydrophobic pocket.

Our observation that the opposite thiazole isomer (i.e., 2) was inactive suggested that the steric and electronic properties of the tricyclic core had a significant effect on the ability to bind FAK. We turned to molecular modeling to gain further insight into the binding mode of 4 and how its potency could be improved (Figure 3). Docking of 4 with FAK (PDB: 6I8Z) revealed two hydrogen-bonding interactions: binding to hinge Cys502 via the aminopyrimidine and binding to the side-chain of Asp564, part of the DFG motif, via the diazepinone carbonyl and thiazole nitrogen. The loss of potency observed for thiazole isomer 2 is likely due to the loss of this hydrogen-bonding interaction. Providing further support for this hypothesis, related benzopyrimidodiazepinones such as XMD8-87 (Figure 2) do not engage FAK.18 The N-methyl amide extends toward the top of the FAK cavity, potentially interacting with Ala452 (Figure 3A); however, it was uncertain whether further modifications would be tolerated. The thiazole 2-methyl extends into the back pocket of the FAK active site, and we hypothesized that longer substituents at this position might benefit from hydrophobic interactions (Figure 3B). Similarly, we proposed that longer substituents on the “bottom” nitrogen of the central ring could extend out of the back end of the U-shaped binding site, potentially gaining beneficial hydrophobic contacts (Figure 3B). Docking analyses of 3, 20, and 26 predicted the same binding mode as 4 (Figure S6).

A summary of SAR studies on the tricyclic core is presented in Table 2. Removal of the thiazole 2-methyl (29) decreased potency roughly 8-fold compared to 1 (IC50 510 vs 62 nM). However, larger substituents at the thiazole 2-position were met with mixed success: ethyl- and isopropyl-substituted analogues 30 and 31 retained activity against FAK, but a phenyl group was not tolerated (32). Whereas N-ethylation at either position of the central ring (34, 35) retained nearly identical potency to 4, other substitutions of the bottom nitrogen led to a slight loss in potency (36, 37). Introduction of an electron-withdrawing group (2-CF333, oxazole 38) sharply decreased potency, further highlighting the importance of the hydrogen bond between the thiazole and Asp564. Interestingly, while 38 is predicted to bind in the same manner as 4, docking of 37 revealed a puckered conformation of the central ring to accommodate the longer N-propyl group (Figure S6).

Table 2. Structure–Activity Relationships of the Tricyclic Core.

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compd R1 R2 R3 FAK IC50 (μM)a cell IC50 (μM)b
4 CH3 CH3 CH3 0.020 ± 0.002c 3.6
29 H CH3 H 0.510 ± 0.035 ND
30 Et CH3 CH3 0.032 ± 0.001 ND
31 i-Pr CH3 CH3 0.059 ± 0.001 ND
32 Ph CH3 CH3 >10 ND
33 CF3 CH3 CH3 0.134 ± 0.001 ND
34 CH3 CH3 Et 0.019 ± 0.001 0.93
35 CH3 Et CH3 0.023 ± 0.001 >10
36 CH3 CH2CF3 CH3 0.068 ± 0.002 ND
37 CH3 n-Pr CH3 0.047 ± 0.001 ND
38d CH3 CH3 CH3 0.525 ± 0.016 >10
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a

IC50 measured using the Z’LYTE assay (ThermoFisher Scientific), as duplicate experiments.

b

IC50 of viability of MDA-MB-231 cells in ultra-low adherent 3D-spheroid suspensions. Values are derived from data presented in Figures 5B and S8 and are representative of n = 3 independent experiments. ND, not determined.

c

n = 4, two independent batches each tested in duplicate.

d

Oxazole instead of thiazole.

With 4 selected as the lead compound, its kinome selectivity was profiled by KINOMEscan screening to confirm that amide N-methylation does not ablate the selectivity initially observed with 1 (Figure 4, Table S1). Although a few additional kinase targets are registered at a 10 μM screening concentration (Figure S2, Table S1), 4 displays “complete” selectivity for FAK at a screening concentration of 1 μM, with an S(35) score of 0.01. In comparison, at an identical screening concentration the S(35) score for defactinib is 0.24.22 Biochemical IC50s were obtained for all nonmutant kinases registering <35% control in the 10 μM KINOMEscan assay (Figure S2), demonstrating that 4 is approximately 100–300-fold selective for FAK. PLK1 proved to be a false positive, with an enzyme IC50 of 8.3 μM, and no cell-cycle disruption was observed during in vitro profiling.

Figure 4.

Figure 4

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KINOMEscan profile of 4.

Seven compounds from the 2-methylthiazole series were evaluated in a mouse-liver microsome stability assay (Table S6). All compounds demonstrated good to excellent microsome stability, with half-lives ranging from 25.5 to >120 min. Lead compound 4 was then submitted for further pharmacokinetic (PK) profiling in mice, with IV (2 mg/kg) and PO (10 mg/kg) doses administered. As shown in Table 3, 4 exhibits low clearance (18.5 mL/min/kg) and is metabolically stable, displaying an average t1/2 of 5.29 h under IV administration. For both routes, detectable levels of drug were observed 24 h after dosing (Tables S7, S8; Figures S4, S5). However, oral bioavailability is limited (%F = 18).

Table 3. Mouse Pharmacokinetic Parameters for 4.

dose parameter 4
2 mg/kg IV CL (mL/min/kg) 18.5
  t1/2 (h) 5.29
  Vss (L/kg) 4.07
10 mg/kg PO Cmax (μM) 0.42
  Tmax (h) 4.00
  AUCinf (h·μg/mL) 1.82
  F (%) 18.3
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We next aimed to explore the biological activity of our FAK inhibitor series. PTK2, the gene that encodes FAK, is a significant genetic dependency in pan-cancer cell line analysis including breast, colorectal, and gastric cancer models (Cancer Dependency Map)23 (Figure S7). We selected MDA-MB-231 cells as a versatile cell line to explore FAK-dependent phenotypes due to their high genetic dependence and overexpression of PTK2 (Figure S7D). Prior studies also indicate that these MDA-MB-231 cells display FAK-dependent migration and invasion potential.24,25 For high-throughput evaluation of the biological effects of our compound series, we compared antiproliferative effects of defactinib, VS-4718, and PF-573228 to 17 representative compounds from our series upon treatment of MDA-MB-231 cells in two-dimensional (2D)-monolayer cultures and ultra-low adherent (ULA) three-dimensional (3D)-spheroid suspensions. We and others have also previously shown that 3D-spheroids serve as better model systems to evaluate drug sensitivity and in vivo tumor physiology.20,26−28 In addition, published FAK agents have limited activity in 2D-monolayer cultures and studies demonstrate improved activity in 3D-culture and in vivo models potentially due to FAK’s kinase-dependent and kinase-independent roles in integrin signaling, adhesion and protein scaffolding.7,29,30

Across the compound series, we observed that MDA-MB-231 cells were more sensitive to FAK inhibition in 3D-spheroids, consistent with prior studies (Figures 5A,B and S8; Tables 1 and 2). VS-4718, defactinib, and PF-573228, which display the most pronounced biochemical potency on FAK, also had the most pronounced antiproliferative effects likely due to a combination of direct FAK inhibitory activity combined with potential multikinase activities. Of our series, 4, 11, 12, 17, and 34 displayed the most pronounced antiproliferative effects in 3D-spheroids, with little to no effects in 2D-monolayer cultures.

Figure 5.

Figure 5

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FAK inhibition decreases proliferation in 3D-spheroid suspensions and migration of breast cancer cells. (A) Scatterplot depicting biochemical IC50 compared to cellular IC50 upon treatment of MDA-MB-231 cells cultured as 2D-adherent monolayers (left plot) or ultra-low adherent 3D-spheroid suspensions (right plot). VS-4718 (VS), defactinib (Def), and PF-573228 (PF) are noted in gray, 4 is noted in red, and the pyrimidothiazolodiazepinone series is noted in black. (B) DMSO-normalized antiproliferation of MDA-MB-231 cells treated with the indicated compounds for 120 h. Cells were cultured as 2D-adherent monolayers (left plot) or ultra-low adherent 3D-spheroid suspensions (right plot). Data are presented as mean ± SD of n = 4 biologically independent samples and are representative of n = 3 independent experiments. (C) DMSO-normalized migration of MDA-MB-231 cells after 24 h under the indicated conditions (nocodazole, Noco). Representative images are provided in Figure S9. Data are presented as mean ± SD of n = 3 biologically independent samples and are representative of n = 3 independent experiments. P values were derived from a two-tailed Student’s t test compared to DMSO control are noted (*P < 0.05, **P < 0.01).

In general, the SAR trends observed for biochemical potency of our series largely translate to activity in 3D-spheroids. For example, 24 and 28 are ∼4-fold less potent than 4 and are >3-fold less potent in the 3D assay. Likewise, 22 shows only modest biochemical potency and does not inhibit proliferation. One exception is the matched pair 20 and 21, where the 2-methoxy 21 is more potent biochemically but demonstrates weaker antiproliferation. This weaker phenotype may stem from a reduced off-target profile that is frequently observed for 2-methoxyanilines.18 Notably, 34, 4, and 35 elicit different biological activity despite possessing nearly identical biochemical potencies. These three compounds have similar kinetic and thermodynamic solubilities, show moderate permeability in a Caco-2 assay, and are potential substrates of P-glycoprotein (P-gp; Tables S8–S10). The improved antiproliferative effect of 34 relative to 4 may stem from the better permeability (Papp,A→B 83 vs 58 nm/s) and lower efflux ratio (2.2 vs 4.1, respectively) of 34. At present, it remains unclear as to why several compounds, such as 14, 16, 23, and 35 display little activity in 3D-spheroids despite being potent biochemical inhibitors.

We further evaluated the effects of 4 on the ability of MDA-MB-231 cells to migrate in response to chemoattraction (serum-containing media). Treatment with 4 led to a statistically significant albeit modest effect on migration of MDA-MB-231 cells. These effects were more pronounced upon treatment with defactinib and nocodazole, an agent that disrupts microtubule polymerization31 (Figures 5C and S9). Together, these data indicate that selective FAK inhibition with 4 leads to modest loss of viability in 3D-suspensions and migratory potential of MDA-MB-231 cells.

To corroborate these findings, we evaluated the effects of FAK inhibition in HT-29 cells, a colorectal adenocarcinoma cell line with PTK2 copy number alterations and elevated expression levels (Figures S7D and S10A). Treatment with 4 led to little or no activity in 2D-monolayer or 3D-suspensions, while more pronounced antiproliferative activity was observed upon treatment with VS-4718, defactinib, and PF-573228 (Figure S10B). While the modest results achieved with 4 are consistent with a prior study evaluating FAK inhibition in HT-29 cells in 2D-monolayer culture and in vivo,32 further testing of potential drug combination strategies may be necessary to achieve enhanced viability effects. For example, combination studies with vemurafenib may be warranted, which has been shown to synergize with FAK inhibitors in these BRAF mutant cells.32

To explore the effects of FAK inhibition in an additional translationally relevant biological context, we assayed the consequences of FAK inhibition in a gastric cancer CDH1–/–RHOAY42C/+ organoid model. We recently demonstrated that FAK, through activation of YAP/TAZ, PI3K/AKT and β-catenin signaling, coordinates diffuse gastric cancer progression.2 Treatment of gastric organoids with 4 led to loss of active, phosphorylated FAK (pFAK Y397), which was more pronounced with defactinib after 24 h (Figure 6A). Defactinib treatment resulted in changes in active, phosphorylated AKT (pAKT S473) and total YAP/TAZ levels, consistent with our prior findings within 24 h,2 while modest effects on pAKT S473 and active, nonphosphorylated YAP were observed with 4 after 48 h treatment (Figures 6A and S11). Differences in pathway responses corresponded with levels of antiproliferative activity. Treatment with 4 led to dose-dependent activity on gastric organoid proliferation, which was more pronounced with defactinib treatment (Figure 6B). Together, these results confirm the potential of targeted FAK inhibition in diffuse gastric cancer.

Figure 6.

Figure 6

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FAK inhibition decreases aberrant signaling and proliferation of gastric cancer organoids. (A) Immunoblot analysis of CDH1–/–RHOAY42C/+ gastric organoids treated with DMSO, 4, or defactinib at the indicated concentrations for 24 h. Data are representative of n = 3 independent experiments. (B) Relative proliferation of CDH1–/–RHOAY42C/+ gastric organoids treated with DMSO, 4, or defactinib (Def) at the indicated concentrations for the indicated time-course. Data are presented as mean ± SD of n = 7–10 biologically independent samples and are representative of n = 3 independent experiments. P values were derived from a two-tailed Student’s t test compared to DMSO control are noted (*P < 0.05, ***P < 0.001).

In summary, we describe the identification and characterization of a selective FAK inhibitor, 4, and we disclose a novel tricyclic core bearing a substituted thiazole. We observe that FAK inhibition leads to loss of viability in breast and gastric cancer 3D-culture model systems, as well as effects on cellular signaling and migration. These effects are milder compared to published FAK inhibitors, in which enhanced effects may be due to additional activities on other kinases. Despite its milder phenotype, 4 may be particularly beneficial as a chemical probe when used in tandem with another kinase inhibitor to study the signaling effects and drug synergy upon dual inhibition, where a clean kinome profile is imperative. As 4 possesses suitable PK properties for studies in mice, further evaluation is required to examine whether the effects in 3D-culture models translate to efficacy in vivo. Our chemical probe serves as a valuable tool to explore the consequences of FAK inhibition and identify potential combination approaches in cancer.

Acknowledgments

We thank members of the Gray laboratory and S. Nabet for helpful discussions. This work was supported by an American Cancer Society Postdoctoral Fellowship PF-17-010-01-CDD (B.N.), Claudia Adams Barr Program in Innovative Basic Cancer Research Award (B.N.), Katherine L. and Steven C. Pinard Research Fund (N.S.G. and B.N.), V Foundation Translational Award (H.Z., K.P., and A.J.B.), NIH grant R01CA224428 (H.Z., K.P., and A.J.B.).

Glossary

Abbreviations

AUCinf

area under the curve extrapolated to infinity

CL

clearance

Cmax

maximum concentration

F

bioavailability

IV

intravenous

PO

per os

t1/2

half-life

Tmax

time at Cmax

Vss

volume of distribution at steady state.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00338.

  • Details of biochemical and biological assays, synthetic procedures, and analytical data (PDF)

Author Contributions

# B.J.G. and B.N. contributed equally to this work. B.J.G., B.N., and N.S.G. conceived of the study. B.J.G. led the medicinal chemistry study and performed compound synthesis and optimization. B.N. led and supervised the biological studies. B.N., M.L.M, H.Z., K.P., and E.K. performed biological assays. C.R.C. contributed to compound synthesis. J.C. performed docking modeling. D.A.S., A.J.B. and N.S.G. supervised the study. B.J.G. and B.N. wrote the manuscript, with edits from N.S.G. and D.A.S. All authors read and approved the manuscript.

The authors declare the following competing financial interest(s): FAK inhibitors noted in this study are subject to patent applications filed by Dana-Farber Cancer Institute. N.S.G. is a Scientific Founder, member of the SAB and equity holder in C4 Therapeutics, Syros, Soltego (board member), B2S, Allorion, Gatekeeper and Petra Pharmaceuticals. J.C. is a consultant for Soltego and equity holder of M3 bioinformatics & technology Inc. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voroni, Arbella, Deerfield and Sanofi. A.J.B receives funding from Bayer, Merck and Novartis and is a co-founder of Signet Therapeutics.

Supplementary Material

ml0c00338_si_001.pdf (4.2MB, pdf)

References

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