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. 2020 Jan 28;11(2):172–178. doi: 10.1021/acsmedchemlett.9b00552

Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent

Upender Velaparthi †,*, Chetan Padmakar Darne †, Jayakumar Warrier ‡, Peiying Liu †, Hasibur Rahaman ‡, Karen Augustine-Rauch †, Karen Parrish †, Zheng Yang †, Jesse Swanson †, Jennifer Brown †, Gopal Dhar ‡, Aravind Anandam ‡, Vinay K Holenarsipur ‡, Kamalavenkatesh Palanisamy ‡, Barri S Wautlet †, Mark P Fereshteh †, Jonathan Lippy †, Andrew J Tebben †, Steven Sheriff †, Max Ruzanov †, Chunhong Yan †, Anuradha Gupta ‡, Arun Kumar Gupta ‡, Muthalagu Vetrichelvan ‡, Arvind Mathur †, Marina Gelman §, Rajinder Singh §, Todd Kinsella §, Anwar Murtaza †, Joseph Fargnoli †, Gregory Vite †, Robert M Borzilleri †
PMCID: PMC7025382  PMID: 32071685

Abstract

graphic file with name ml9b00552_0009.jpg

Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

Keywords: TGFβR1, immuno-oncology, imidazo-pyridine, imidazo-pyridazine, intermittent dosing

Immuno-oncology has emerged as one of the most promising areas of research in transforming cancer treatment.1,2 Antibodies that target immune checkpoints such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or the PD-1 ligand (PD-L1) elicit impressive long-term durable remissions in multiple tumor types.3 However, limitations exist as only a fraction of patients respond to therapy,4 and therefore, increasing attention has focused on the identification of validated predictive biomarkers to help select patients who are likely to respond to a given therapy. Overexpression of transforming growth factor β (TGFβ) in the tumor microenvironment (TME) has been reported to be a determining factor in tumor T cell exclusion and poor response to PD-1/PD-L1 blockade.5 To that end, the combination of TGFβ inhibition with immune checkpoint blockade in murine tumor models induced complete and durable responses in otherwise unresponsive tumors.6,7

TGFβ is a multifunctional cytokine that regulates a wide variety of biological processes that include cell proliferation, differentiation, migration and adhesion, and extracellular matrix modification including tumor stroma and immunosuppression.8,9 Besides promoting epithelial-to-mesenchymal transition, invasion, and metastasis of tumor cells, TGFβ plays a critical role in regulating adaptive immunity inducing regulatory T cells (Tregs) which suppress immune surveillance. The active form of TGFβ is a dimer that signals through the formation of a membrane-bound heterotetramer composed of the serine/threonine type 1 and type 2 receptors, TGFβR1 and TGFβR2, respectively.10 Upon binding of TGFβ to TGFβR2, phosphorylation of TGFβR1 occurs in the glycine and serine rich “GS region” of the protein activating a signaling cascade through the effector molecules, Smad2 and Smad3. TGFβR1 phosphorylates Smad2 and/or Smad3 (RSmads) and forms a complex with Smad4. These complexes then translocate to the nucleus where they elicit a wide variety of transcriptional responses resulting in altered gene expression. Activated TGFβ can also trigger SMAD-independent pathways, such as mitogen-activated protein kinases (MAPK, AKT etc.) to regulate a large variety of functions in different cellular and tissue contexts.11,12 Alterations in TGFβ signaling are associated with a wide variety of human disorders including fibrosis, inflammation, skeletal, muscular, and cardiovascular disorders as well as cancer. In humans, dysregulated TGFβ signaling can occur in the germline or arise spontaneously leading to various cancer types.

Given the important role of TGFβ signaling in antitumor immunity, numerous therapeutic approaches13,14 including antisense oligonucleotides, ligand traps, monoclonal antibodies, and small molecule receptor kinase inhibitors are currently being explored to overcome TGFβ-mediated immunosuppression. Three small molecule TGFβR1 inhibitors, Galunisertib (1, LY2157299 monohydrate), Vactosertib (2, EW7197), and LY3200882 (3) are currently being evaluated in clinical trials (Figure 1). Compound 1 promoted antitumor immunity leading to durable complete response in combination with checkpoint blockade in mouse tumor models.15 Initial cardiovascular toxicity concerns were addressed with an intermittent dosing schedule (2 weeks on and 2 weeks off during a 28 day cycle) which provided a therapeutic margin enabling clinical dosing, and it is currently under development in combination with checkpoint inhibitors in patients with NSCLC, HCC, and pancreatic cancer.16 To date, no adverse cardiovascular findings have been reported for 1 in the clinic.

Figure 1.

Figure 1

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TGFβR1 inhibitors in clinical trials

We previously described TGFβR1 selective inhibitors derived from pyrrolotriazine17 and 4-azaindole18 scaffolds. In continuation of our interest in identifying potent and selective TGFβR1 inhibitors, the kinase selectivity data of proprietary compound collections was interrogated to identify additional leads.19,20 These efforts revealed the imidazo-pyridine chemotype 4 (Figure 2) which demonstrated good affinity for TGFβR1. After incorporating substituents onto the imidazole nitrogen to dial out off-target kinase activities and installing 2-pyridyl moiety at the gate-keeper region, compound 5 demonstrated excellent potency in the biochemical binding (TGFβR1 IC50= 0.010 μM) assay. A 1.83 Å resolution cocrystal structure of compound 5 bound to the ATP binding site of TGFβR1 kinase domain (T204D mutant) revealed key interactions with the protein. As highlighted in Figure 3, imidazo-pyridine nitrogen makes a key hydrogen bond interaction with His283 within the hinge region. The imidazole engages hydrogen bond interaction with conserved Lys232 and the 2-pyridyl group in the back pocket forms a water-mediated hydrogen bond with Tyr249.21 Interestingly, an additional hydrogen bond interaction was observed with the hydrogen of the difluoromethyl group22 with Lys337. Although compound 5 demonstrated cellular activity in TGFβ-dependent functional assays (MINK SMAD nuclear translocation IC50 = 0.42 μM and NHLF SMAD2 IC50 = 0.09 μM), it suffered from poor metabolic stability in rat liver microsomes (31% remaining after 10 min incubation). Since the cocrystal structure of compound 5 also indicated that an open pocket was present underneath the imidazo-pyridine ring, we hypothesized that appropriate substitutions at the C-3 position of imidazo-pyridine could improve both potency and metabolic stability. Accordingly, several groups were examined at the C-3 position and appending a primary carboxamide modestly improved its metabolic stability (compound 6), but this improvement did not translate into good mouse oral exposure (2 μM·h AUC0–24 h at 10 mg/kg with a very high peak to trough ratio of 36).

Figure 2.

Figure 2

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Evolution of compounds en route to BMS-986260.

Figure 3.

Figure 3

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X-ray cocrystal structure of compound 5 bound to the TGFβR1 kinase domain (T204D mutant; 1.83 Å). PDB accession code: 5QTZ.

After extensive structure–activity relationship (SAR) exploration, replacing the imidazo-pyridine with an imidazo-pyridazine core and changing the 2-pyridyl to a 4-fluoro phenyl at the gate-keeper region provided compound 7 which further improved its metabolic stability resulting in very good oral exposure of 28 μM·h AUC0–24 h at 10 mg/kg with relatively low peak to trough ratio of 6.3. Although compound 7 demonstrated robust functional activity in TGFβ-dependent cell lines, it unfortunately could not be advanced further due to high efflux (∼23) in the Caco-2 bidirectional assay. Interestingly, modifying the carboxamide group to less polar cyano at the 3-position (compound 8) not only alleviated the efflux issue but also substantially improved selectivity for the TGFβR1 over the RII isoform (Table 1). However, this modification negatively affected aqueous solubility. In an effort to improve aqueous solubility, we turned to N1 substitutions on the imidazole ring and installed a variety of solubilizing groups. A hydroxyethyl group on the imidazole (9) improved crystalline solubility (∼138 μg/mL at pH = 6.5) but was found to be somewhat weaker in cell based assays despite the hydroxyl group maintaining the hydrogen bond with Lys337. In order to further balance potency, efflux, and solubility, a chloro group was introduced next to fluoro on the phenyl ring to provide compound 10 (BMS-986260) which displayed the best balance of potency, selectivity, pharmacokinetics (PK), and solubility. The cocrystal structure of compound 10 (Supporting Information) bound to the kinase domain maintained all the known interactions with the protein while the hydroxyethyl group on the imidazole forms a hydrogen bond with Lys337.

Table 1. Profiling of Compounds 4–11.

Compound TGFβR1 (IC50, μM) TGFβR2 (IC50, μM) MINKa SMAD translocation (IC50, μM) NHLFb SMAD translocation (IC50, μM) Metabolic Stability (human, rat, mouse% remaining)
4 0.017 5.71 NT NT NT
5 0.0010 12.9 0.42 0.09 78,31,54
6 0.0007 0.82 0.56 0.13 97,74,65
7 0.0009 2.93 0.66 0.42 100,100,100
8 0.0016 >15 0.20 0.08 75,96,89
9 0.0067 >15 0.8 0.35 93,100,86
10 0.0016 >15 0.35 0.19 77,91,81
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a

Inhibition of phosphorylation and subsequent nuclear translocation of SMAD in mink lung epithelial (MvLu1) cells.

b

Inhibition of phosphorylation and subsequent nuclear translocation of SMAD in normal human lung fibroblasts (NHLF) cells.

The lead compound 10 was fully profiled in vitro and in vivo, as shown in Table 2. It is a highly potent TGFβR1 inhibitor in both human (Kiapp = 0.8 nM) and mouse (Kiapp = 1.4 nM) biochemical assays, and surprisingly, it displayed exquisite selectivity for TGFβR1 over its isozyme TGFβR2, as well as in a panel of more than 200 kinases examined. As shown in Figure 4, it showed a remarkable selectivity profile of >50-fold versus relevant kinases. Consistent with its biochemical potency, compound 10 also demonstrated modulation of the target in multiple TGFβ-dependent cellular assays. It inhibited TGFβ mediated nuclear translocation of pSMAD2/3 in MINK and NHLF cells lines with an IC50 of 350 nM and 190 nM, respectively. It also inhibited TGFβ induced SMAD phosphorylation in NIH3T3 cell line, primary human T cells, and mouse and human whole blood. Additionally, compound 10 inhibited TGF-β mediated induction of regulatory T cell (Treg) by downregulation of FOXP3 expression and a repression of CD25 with an IC50 of 230 nM.

Table 2. Detailed Profile of Compound 10a.

Assay Result
Hu T-cell pSMAD3 IC50 (μM) 0.15
NIH3T3 pSMAD3 IC50 (μM) 0.05
Hu Treg FoxP3+ IC50 (μM) 0.23
AMES result Negative
LM T1/2 (NADPH, min) mouse, rat, dog, human 28, 50, 37, 23
LM T1/2 (UGT/UDPGA, min) mouse, rat, dog, human >120, >120, 92, >120
Hepatocyte T1/2 (min) mouse, rat, dog, human 76, 320, 62, 54
Protein binding (% free fraction): mouse, rat, dog, human 12, 10, 13, 10
rCYP 450 inhibition IC50 (μM) 1A2, 2C8, 2C9, 2C19, 2D6, 3A4 >20, >20, >20, >20, >20, >20, >20
hERG EP IC50 (μM) >10
PXR (EC50, μM & Ymax) >24/44
aq. solubility at pH 6.5 (μg/mL) 47
In vitro safety panel (IC50) >25 μM except PDE4 (11 μM) out of 46 tested
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a

The TGFβR1, TGFβR2, MINK SMAD, and NHLF SMAD IC50s for compound 10 are reported on the last line of Table 1.

Figure 4.

Figure 4

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Profile of compound 10 across more than 200 kinases in a broad screening panel, with kinases showing IC50 values <10 nM (black circle), <100 nM (red circle), <1000 nM (yellow circles) or >1000 nM (blue squares). Selectivity was determined from binding data generated using fluorescent probe displacement assay (HTRF). Illustration reproduced courtesy of Cell Signaling Technology Inc.

Having demonstrated excellent functional activity in various TGFβ-dependent cell lines, compound 10 was further profiled for its PK properties and liability assessment. Incubation in liver microsomes showed excellent stability across multiple species (T1/2 > 120 min for mouse, rat, and human and 92 min for dog). The compound has good intrinsic permeability in Caco-2 cells (272 nm/s) with low efflux ratio (2.5) and was well absorbed following oral administration from solution formulation. In protein binding assays, compound 10 has a free fraction of 10% in human serum and 12%, 10%, and 13% in mouse, rat, and dog, respectively. The compound has low potential for drug–drug interactions (DDI) since it is neither a cytochrome P-450 (CYP) inhibitor with IC50 values of >20 μM against six major isozymes (1A2, 2C8, 2C9, 2C19, 2D6, 3A4) nor a CYP inducer at concentrations up to 24 μM. The selectivity of compound 10 was evaluated by screening against a 46 panel of receptors, ion channels, transporters, kinases, and proteases. No apparent activity was identified (all >25 μM except PDE4, 11 μM) suggesting a low potential for off-target effects. It was also clean in hERG, Ames, and cellular cytotoxic panels (>25 μM in proliferation assays).

Good overall pharmacokinetic parameters were observed with compound 10 in preclinical studies across multiple species (Table 3). Consistent with the observed low rate of metabolism in the microsomal assays, compound 10 displayed low to moderate in vivo clearance in mouse, rat, and dog with human clearance predicted to be low (4 mL/min/kg). It exhibited a high volume of distribution which ranged from 1.1 to 4.5 L/kg in preclinical species and a long half-life of 9.1 h in mouse and 5 h in dog. It displayed maximum oral bioavailability in mouse and rat (F = 100%) and near maximum oral bioavailability in dog (F = 93%).

Table 3. Pharmacokinetic Parameters for Compound 10.

Parameter Mousea Ratb dogc
Dose (mg kg–1) iv/po 5/10 5/10 1/5
Cmax (μM) po 16 12.7 11.2
AUCtotal (μM·h) iv/po 26.3/80.5 39.6/90.8 7/35
Tmax (h) po 0.3 1.1 0.67
T1/2 (h) iv 9.1 5.7 5.0
MRT (h) iv 9.0 7.2 3.1
CL (mL/min/kg) iv 8.3 5.6 6.4
Vss (L/kg) iv 4.5 2.4 1.1
F po (%) >100 >100 93
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a

Male Balb/C mice (n = 3), 70% 25 mM acetate buffer, pH 4.0, 5% ethanol, 25% PEG 400.

b

Male Sprague–Dawley rats (n = 3), PEG400 solution.

c

Male Beagle dogs (n = 2) pretreated with pentagastrin, 5% ethanol, 45% PEG400, 50% 25 mM acetate buffer, pH 4.0 (po); 5:45:50 EtOH/PEG400/saline, 1 mL/kg (iv).

Compound 10 was prepared via the synthetic sequence outlined in Scheme 1. It was envisioned that the construction of the central 1,4,5-trisubstituted imidazole ring could be achieved using the Van Leusen three-component coupling reaction23 which would require the synthesis of the tosyl isocynide 13 fragment and the aldehyde 18. The synthesis of 13 was achieved in two steps from commercially available aldehyde 11, which was converted to tosylformamide 12. Dehydration of intermediate 12 provided the desired fragment 13. Synthesis of aldehyde 18 was commenced from commercially available 6-bromopyridazine-3-amine (14) which was condensed with N,N-dimethylformamide dimethylacetal to furnish enamine 15. Treatment of 15 with bromoacetonitrile in the presence of Hunig’s base provided the imidazo-pyridazine core 16. Stille coupling with tributyl(vinyl) tin followed by osmium tetroxide mediated oxidative cleavage provided aldehyde 18. Having synthesized the two required fragments, aldehyde 18 was first condensed with 2-amino ethanol to generate imine 19, which upon treatment with isocynide 13 smoothly provided the final compound 10.

Scheme 1. Synthesis of Compound 10.

Scheme 1

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Reagents and conditions: (a) TolSO2H, formamide, TMSCl, MeCN, 50 °C, 63%; (b) POCl3, 2,6-lutidine, THF, 0 °C, 72%; (c) DMF-DMA, 100 °C, 91%; (d) BrCH2CN, DIPEA, MeCN, 80 °C, 90%; (e) tributyl(vinyl) tin, Pd(PPh3)4, 1,4-dioxane, 105 °C, 76%; (f) OsO4·H2O, NaIO4, 1,4-dioxane, H2O, 76%; (g) 2-aminoethanol, MgSO4, DCM, RT, 97%; (h) K2CO3, DMF, RT, 94%.

Due to the encouraging in vitro profile and excellent PK properties, the antitumor efficacy of compound 10 in combination with anti PD-1 was evaluated in the MC38 murine colon carcinoma syngeneic model to determine if TGFβ inhibition enhances the antitumor activity of the PD-1 blockade. C57/BL6 mice were subcutaneously injected with 0.1 mL tumor cells (1 × 107 cells/mL) into the right flank, and tumor bearing animals were sorted and randomized when tumors reached the target size of approximately 100 mm3, typically by day 5. MOPC-21 is a commercially available nonreactive in vivo mouse monoclonal antibody IgG1 isotype which was used as a control for anti-PD-1 and dosed on the same schedule as anti-PD-1 in each experiment. As expected, anti-PD-1 antibody treatment (10 mg/kg, IP, Q4D, 3 doses) resulted in only partial response. Daily oral administration of compound 10 alone as a monotherapy up to 15 mg/kg for 28 days did not result in any tumor growth inhibition (Figure 5). However, combination of compound 10 with anti-PD-1-antibody demonstrated robust antitumor efficacy with a 90–100% complete response (CRs) at all 3 dose levels (3.75, 7.5, and 15 mg/kg) (Figure 5). This efficacy correlated with pSMAD2/3 inhibition and increase in intratumoral CD8+ T-cells. More importantly, the curative effect of this combination therapy was found to be durable with a majority of responding mice in the combination groups staying tumor-free for ten doubling times after cessation of treatment. In a rechallenge study, cured mice from anti-PD-1 combination studies rejected newly implanted MC38 cells as compared to naive mice but did not reject the implanted LL2 cancer cells, demonstrating that the antitumor efficacy was immune-mediated with memory response (Figure 6). Additionally, compound 10 inhibited metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model (Supporting Information).

Figure 5.

Figure 5

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Antitumor activity of compound 10 alone and in combination with anti-PD-1 antibody using a daily dosing schedule in the MC38 syngeneic tumor model. Compound 10 was administered orally (PO) every day for 28 days. Anti-PD-1 antibody was administered intraperitoneally (IP) every 4 days for three doses.

Figure 6.

Figure 6

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Tumor growth following MC38 or LL2 rechallenge study in cured mice treated with compound 10 in combination with anti-PD1 antibody. Treatment of compound 10 in combination with anti-PD-1 antibody induces long-term memory response.

Continuous dosing of small molecule TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities including valvulopathy and aortic pathologies in preclinical species.24 In order to assess the tolerability of compound 10, daily oral dosing in dogs and rats was conducted in 10-day exploratory toxicology studies. At doses that provided exposures similar to the 3.75 mg/kg efficacious mouse exposure (1 mg/kg in rats, and 5 mg/kg in dogs) CV toxicity, including valvulopathy and aortic pathology, was encountered, thereby preventing further progression of compound 10 on a daily dosing schedule. Since compounds 1 and 2 are administered using drug holiday schedules in the clinic and appear to have mitigated on-target CV toxicity, a variety of intermittent dosing regimens were evaluated with compound 10 to improve the therapeutic index. An efficacy study in combination with anti-PD-1 was conducted using an intermittent dosing regimen of 3 days on and 4 days off that resulted in similar efficacy as daily dosing at 3.75 mg/kg (Figure 7). This efficacy was correlated with pSMAD2/3 inhibition and increase in intratumoral CD8+ T-cells. Robust efficacy of compound 10 in combination with anti-PD-1 in an intermittent dosing regimen also achieved similar progression free survival (PFS) as seen with daily dosing (data not shown). Furthermore, this intermittent dosing regimen of 3 days on and 4 days off was also successful at mitigating CV toxicities with compound 10 in both rat and dog in one month pivotal toxicology studies.25

Figure 7.

Figure 7

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Antitumor activity of compound 10 in combination with anti-PD-1 antibody using an intermittent dosing in the MC38 CRC syngeneic tumor model. Compound 10 was administered orally (PO) either every day (groups 3 and 5) or 3 days on 4 days off (groups 4 and 6) for 28 days. Anti-PD-1 antibody was administered IP every 4 days for three doses.

In conclusion, a potent and selective TGFβR1 inhibitor, compound 10, was identified from a novel imidazole containing imidazo-pyridine lead through a series of SAR studies primarily focused on improving potency, PK attributes, and solubility. Compound 10 was found to be orally efficacious in combination with anti-PD-1 antibody treatment in the mouse MC38 tumor model. Since continuous dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule was explored in the anti-PD1 combination efficacy studies. An intermittent dosing regimen of 3 days on and 4 days off, which demonstrated mitigation of CV toxicities in one month dog and rat toxicology studies, provided similar efficacy as daily dosing with acceptable safety margins. These combined results supported further advancement of compound 10 as a development candidate.

Acknowledgments

We gratefully acknowledge our colleagues Ananta Karmakar, Gopikumar Indasi, and Radhakrishnan Vignesh for the scale-up of compound 10 and our colleagues in the Lead Evaluation group for their assistance during SAR study. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute.

Glossary

Abbreviations

TGFβR1

transforming growth factor β receptor-1

IO

immuno-oncology

PD-L1

programmed death-ligand 1

SMAD

mothers against decapentaplegic homologue

tMSAD

total SMAD

LM

liver microsomes, Hu, human

NADPH

nicotinamide adenine dinucleotide phosphate

UGT

uridine 5-diphospho-glucuronosyl transferase

UDPGA

uridine diphosphoglucuronic acid

FOXP3

foxhead box P3

rCYP450

recombinant cytochrome P450

hERG PC

human ether-a-go-go-related patch clamp assay

PXR

pregnane X receptor

PK

pharmacokinetics

QD

once a day

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00552.

  • Full experimental details for key compounds, biological protocols, screening protocols, and crystallography details (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml9b00552_si_001.pdf (783.7KB, pdf)

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