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. 2026 Jun 19;17(7):1547–1554. doi: 10.1021/acsmedchemlett.6c00114

The Development of UM-232, a Covalent STING Antagonist

Leonard Barasa †,‡, Leo DeOrsey †,‡, Maeve D O’Reilly †,‡, Sara E Cahill §, Shruti Choudhary †,‡, Akumalla Allabaji ∥, Srinivasa Rao Vidadala ∥, Sujit Kumar Sarkar ∥, Santoshkumar N Patil ∥, Jeffrey Hale ⊥, Fiachra Humphries §, Paul R Thompson †,‡,*
PMCID: PMC13358945  PMID: 42445028

Abstract

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is a central regulator of innate immunity, sensing cytosolic DNA and initiating inflammatory signaling. Aberrant activation of this pathway drives autoimmune and inflammatory pathologies, positioning STING as a compelling therapeutic target. Here, we describe the structure–activity relationship (SAR)-guided optimization of LB-246 to yield UM-232, a next-generation STING inhibitor with markedly improved potency and selectivity. Rational design incorporated two key modifications: substitution of the N-α amide with an isosteric triazole and replacement of the C-terminal benzimidazole with a spirocyclic piperidine-oxetane moiety. These changes conferred an 8-fold increase in cellular potency, robust inhibition of STING oligomerization, and enhanced metabolic stability. Incorporation of an α-methyl chloroacetamidine warhead further augmented activity. Collectively, UM-232 establishes a promising chemical scaffold for therapeutic development targeting STING-driven autoimmune and inflammatory disorders.

Keywords: Stimulator of interferon genes, oligomerization, small-molecule inhibitor, TBK1

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The cyclic GMP-AMP synthase (cGAS) - Stimulator of Interferon Genes (STING) pathway plays a central role in innate immunity by detecting cytosolic double-stranded DNA and initiating proinflammatory signaling. , Upon DNA binding, cGAS catalyzes the synthesis of 2’3′-cyclic GMP-AMP (cGAMP), a second messenger that binds and activates STING. Upon activation, STING, a transmembrane protein localized to the endoplasmic reticulum (ER), translocates to the Golgi apparatus and subsequently to lysosomes for degradation. − During this trafficking, STING recruits and activates TANK-binding kinase 1 (TBK1) and IκB kinase (IKK) via its C-terminal tail, leading to the phosphorylation and activation of the transcription factors IRF3 and NF-κB. Consequently, the expression of type I interferons and proinflammatory cytokines is increased. ,

STING is a central mediator of innate immunity, broadly expressed in diverse immune cells and tissues. Dysregulated or chronic STING signaling has been implicated in a wide range of immune and nonimmune disorders. For example, aberrant STING activation is associated with Aicardi-Goutières syndrome (AGS), − systemic lupus erythematosus (SLE), , STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus, and amyotrophic lateral sclerosis (ALS). − These associations have spurred intense interest in developing STING inhibitors. Current strategies include compounds that (1) block palmitoylation, − (2) prevent cGAMP from binding, − (3) promote STING degradation via the proteosome, − and (4) block oligomerization which is essential for the activation of STING signaling. − Despite these advances, no STING inhibitor has entered clinical trials, underscoring the urgent need for novel and effective antagonists.

Herein, we report the structural optimization of LB-246. Guided by a structure–activity relationship (SAR) analysis, we synthesized UM-232 (Figure A,B), a more potent analog. Synthetic methods and compound characterizations are provided in the Supporting Information (Schemes S1–S15, Figures S1–S15). UM-232 is 8-fold more potent than LB-246 in a STING-responsive cell-based assay and shows minimal cytotoxicity at concentrations below 40 μM, supporting its safety profile. In addition to enhanced potency, UM-232 inhibited STING oligomerization and demonstrated excellent metabolic stability, suggesting favorable pharmacokinetic properties and strong potential for further therapeutic development.

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(A) Chemical structure of LB246 and its SAR scaffold. (B) Half-maximal effective concentration (EC50) values for LB246 analogs in THP-1 cells overexpressing wild-type STING (R232 variant). Data are shown as mean ± SEM (n = 3).

We previously reported that BB-Cl-amidine, a widely used Protein Arginine Deiminase (PAD) inhibitor, is a STING inhibitor. During our initial efforts to identify an analog that preferentially inhibits STING signaling but not the PADs, we described the design and synthesis of LB-246, which incorporates an α-methyl-chloroacetamidine warhead in place of the chloroacetamidine warhead present in BB-Cl-amidine. Despite its limited potency (EC50 = 20 μM), we felt that the low reactivity/high proteome wide selectivity of the α-methyl-chloroacetamidine warhead offered substantial benefits. Therefore, we initiated optimization efforts on LB-246 by replacing the N-α amide with an isosteric triazole moiety and substituting the benzimidazole scaffold (Figure A).

Following synthesis, the inhibitory potency of the derivatives was evaluated relative to LB-246 using a cell-based reporter assay. , THP1-Dual cells overexpressing wild-type STING were pretreated with compound (1 h) and then stimulated with diABZI (500 nM, 24 h). These cells express Lucia luciferase under an IRF3-responsive promoter and Secreted Embryonic Alkaline Phosphatase (SEAP) under an NF-κB-responsive promoter. STING activation by diABZI induces luciferase secretion, which was quantified as a measure of pathway activation. Inhibition was assessed by the reduction in luciferase activity, and dose–response curves were used to determine EC50 values (mean ± SEM, n = 3, Figure S16).

Our initial strategy involved substituting the benzimidazole moiety with pyridinylmethylene amide derivatives, leading to the synthesis of UM-223, UM-224, and UM-225. In the cell-based assay, UM-223 and UM-224 demonstrated a 2- to 3-fold increase in potency relative to LB-246, whereas UM-225 showed no detectable activity (Figure B). These differences may be attributed to the spatial orientation of the pyridine nitrogen, potentially affecting its role as a hydrogen bond acceptor within the binding pocket. Subsequent replacement with a pyridazinylmethylene amide yielded UM-226, which exhibited a 3-fold increase in potency. Similarly, substitution with thiazolylmethylene and difluoromethylpyrazol amides produced UM-230 and UM-227, respectively. UM-230 demonstrated a 4-fold increase in potency, while UM-227 was inactive (Figure B).

Next, we replaced the benzimidazole scaffold with heterocyclic and amide substituents that increase sp3 character. These modifications included spirocyclic piperidine-oxetane and pyrrolidine-furan amide moieties; spirocycles have gained prominence in medicinal chemistry due to their rigid, three-dimensional architecture, which can enhance target engagement and pharmacokinetic properties. Here, it was expected that these motifs would engage the STING binding pocket through unique spatial interactions, potentially contributing to improved potency and selectivity. Relative to the reference compound LB-246, UM-232 demonstrated an 8-fold enhancement in potency, whereas UM-233 exhibited a 3-fold improvement (Figure B). Further modifications included the introduction of difluoroazabicyclohexane, pyrrolopyrazinone, and furopyrrole groups, resulting in UM-234, UM-235, and UM-236. UM-234 and UM-235 demonstrated a 2- to 3-fold increase in potency, whereas UM-236 showed a 4-fold enhancement in activity in STING cell-based assays compared to LB-246 (Figure B). Additionally, replacing the benzimidazole moiety with morpholine, pyrrolidine, dimethyl, and methyl amides yielded UM-241, UM-240, UM-239, and UM-238, respectively. UM-240 and UM-241 exhibited a 3–4-fold increase in potency, while UM-239 and UM-238 displayed activity comparable to LB-246 (Figure B).

Given the notable increase in potency observed with UM-232, we further evaluated this compound. As an initial step, we assessed the cytotoxicity of UM-232 in THP1 Dual cells, where it exhibited minimal toxicity at concentrations below 40 μM (Figure S17), supporting its suitability for further biological evaluation. To investigate proteome-wide reactivity, we synthesized an alkyne-tagged analog, UM-232-Al (Figure A). We first confirmed that UM-232-Al retained STING inhibitory activity using a cell-based assay in THP1-Dual cells expressing wild-type STING. UM-232-Al effectively blocked STING signaling with potency comparable to that of UM-232 (Figure B). We next evaluated the proteome-wide reactivity and target engagement of UM-232-Al. HEK-STING cells were treated with UM-232-Al for 4 h, followed by cell lysis and conjugation of probe-labeled proteins to biotin-azide via copper-catalyzed azide–alkyne cycloaddition (CuAAC, Figure C). In-gel analysis revealed minimal off-target labeling by UM-232-Al compared to BB-Cl-yne, the alkyne analog of BB-Cl-amidine, indicating superior selectivity (Figures D). To confirm direct STING engagement, probe-labeled proteins were enriched using streptavidin agarose beads and analyzed by Western blotting, and this analysis detected covalent modification of STING by UM-232-Al in cells (Figure E).

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(A) Structures of UM-232 and the alkyne analog UM-232-Alkyne (UM-232-Al). (B) Comparison of EC50 values between the parent compound and the corresponding alkyne structure. (C) STING labeling workflow by clickable probes. (D) Proteome-wide reactivity of BB-Cl-yne (Alkyne of BB-Cl-amidine) and UM-232-Al. Dose-dependent protein-labeling visualized by Western blotting Streptavidin IRDye 800CW and anti-STING antibody. (E) Detection of STING enrichment after pulldown using streptavidin agarose. (F) Site of covalent modification. HEK293T cells expressing wild-type, C292A, or C309A mutants were incubated with UM-232-Al (5 μM) for 1 h, followed by click chemistry conjugation with biotin–azide. Labeled proteins were enriched using streptavidin agarose and analyzed by immunoblotting with an anti-STING antibody.

Several covalent inhibitors of STING have been reported, targeting distinct cysteine residues to modulate pathway activation. The most frequently modified site is C91, where covalent engagement by inhibitors such as H-151 blocks STING palmitoylation. By contrast, BB-Cl-amidine, LB244, and UM-200 inhibit STING oligomerization through modification of either C292 or C309. , To identify the residue modified by UM-232, HEK293T cells expressing STING C292A , or C309A , mutants were treated with UM-232-Al, an alkyne-tagged analog of UM-232. Both mutant proteins were robustly expressed (Figure F). Mutation of either C292 or C309 markedly reduced probe incorporation, indicating that one or both residues contribute to covalent engagement by UM-232. Notably, C292 and C309 are spatially proximal in the STING structure, and mutation of one residue appears to influence modification at the other site.

To further evaluate the functional activity of UM-232, its ability to inhibit STING signaling was examined in mouse macrophages. Wild-type bone marrow–derived macrophages (WT BMDMs) were pretreated with UM-232 (2.5 or 5 μM) or DMSO vehicle prior to stimulation with the STING agonist diABZI (500 nM). UM-232 suppressed diABZI-induced transcription of Ifnb, Il6, and Cxcl10 in a dose-dependent manner (Figure A–C). Next, we confirmed that UM-232 directly impacts STING signaling by measuring its effect on IRF3 and TBK1 phosphorylation. For these studies, WT BMDMs were pretreated with UM-232 (5 μM) for 1 h and then treated with diABZI-3, a synthetic STING agonist, for 0–120 min or 0–180 min. The levels of phospho-IRF3 and phospho-TBK1, were notably reduced following treatment with UM-232 (Figure D,E). We also evaluated the effect of UM-232 on the formation of STING oligomers by immunoblot analysis of native and reduced fractions of lysates from WT BMDMs pretreated with UM-232 (5 μM) for 1 h followed by treatment with diABZI-3 for 30 min. The data indicates that UM-232 blocks STING oligomerization (Figure F). Finally, we assessed the metabolic stability of UM-232 in human and mouse liver microsomes. UM-232 exhibited high stability in the human system and slightly greater stability than the positive control in the mouse system, indicating a favorable metabolic profile (Table S1).

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UM-232 inhibits STING activation and downstream signaling in vitro. (A–C) qPCR analysis of Ifnb, Il6, and Cxcl10 mRNA expression in bone marrow-derived macrophages (BMDMs) pretreated with UM-232 and subsequently stimulated with diABZI (500 nM) for 2 h. Data represent mean ± SD (n = 3 biological replicates, each measured in duplicate). **p < 0.0001 by one-way ANOVA. (D) Immunoblot analysis of phosphorylated IRF3 in whole-cell lysates from wild-type BMDMs pretreated with UM-232 (5 μM, 1 h) followed by stimulation with diABZI for 0–120 min. (E) Immunoblot analysis of phosphorylated TBK1 in whole-cell lysates from wild-type BMDMs pretreated with UM-232 (5 μM, 1 h) followed by stimulation with diABZI for 0–180 min. (F) Immunoblot analysis of STING in nonreducing and reducing lysate fractions from wild-type BMDMs pretreated with UM-232 (5 μM, 1 h) and stimulated with diABZI for 30 min.

Aberrant activation of STING has been implicated in a range of autoimmune and inflammatory disorders, making STING antagonists attractive therapeutic candidates. In this study, we developed a systematic SAR to optimize the parent compound, LB-246, leading to the development of UM-232. UM-232 demonstrated an 8-fold increase in potency compared to LB-246 in STING cell-based assays. Importantly, it retained robust activity against the most prevalent human STING variant (R232), exhibited high selectivity for STING, inhibited STING oligomerization and showed improved metabolic stability, highlighting its potential for further preclinical development.

The ability of UM-232 to inhibit STING signaling via covalent modification of C292 or C309 is notable, as residues 281–297 have been implicated in STING degradation. These findings suggest that modification within this region disrupts STING oligomerization. Further studies are needed to define the precise mechanism by which these modifications impair STING activation.

In summary, STING plays a central role in the pathogenesis of several autoinflammatory and autoimmune disorders, including AGS, SLE, ALS, and SAVI. These findings underscore the therapeutic potential of targeting the STING pathway. Here, we report the discovery of UM-232, a small molecule incorporating a mild electrophilic warhead, which effectively inhibits STING signaling in human cells. Collectively, our results highlight UM-232 as a promising candidate for the treatment of STING-associated inflammatory and autoimmune diseases.

Reagents and Compound Synthesis

Synthetic methods and characterization of the STING inhibitors and probes described in the manuscript are described in the Supporting Information (Schemes S1–S15, Figures S1–S17). All other reagents were obtained from commercial sources, and their specific sources are indicated below or in the Supporting Information.

Ethical Statement

All animal experiments were conducted in accordance with institutional guidelines and approved by the Institutional Animal Ethics Committee (IAEC) of Syngene International Ltd. under protocol numbers SYNGENE/IAEC/1632/10–2024 and SYNGENE/IAEC/1681/03–2025.

STING inhibition assay in THP-1 Dual Cells

Wild-type THP1-Dual KI-hSTING-R232 cells, were obtained from InvivoGen (Catalog No. thpd-r232). Cells were cultured in RPMI 1640 supplemented with 2 mM l-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum, 100 μg/mL Normocin, and Pen-Strep (100 U/mL–100 μg/mL). For selection, Blasticidin (10 μg/mL) and Zeocin (100 μg/mL) were alternately included in the growth medium every other passage. Upon reaching confluence, cells were pelleted and resuspended in phenol red-free test medium (RPMI 1640, 2 mM l-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum, Pen-Strep). Cell density was adjusted to 1.05 × 106 cells/mL using an automated cell counter. A volume of 24 μL per well was plated in 384-well Greiner plates (Catalog No. 781098). Compounds were tested at final concentrations of 40, 20, 10, 5, 2.5, 1.3, 0.63, 0.31, 0.16, and 0.08 μM (1% DMSO final). After 1 h incubation at 37 °C, diABZI (500 nM) was added to all compound-containing and positive control wells. Negative controls contained 1% DMSO only. Plates were incubated at 37 °C for 24 h. Luciferase activity was measured by adding 75 μL of QUANTI-Luc reagent (InvivoGen) diluted in 30 mL water to each well, and luminescence was recorded within 5 min using a PerkinElmer EnVision 2105 plate reader. Data were normalized to DMSO-only controls (without diABZI), and percent activation was calculated relative to diABZI-only controls. All compounds were tested in quadruplicate.

Proteome-Wide Selectivity Studies

HEK-293T cells overexpressing STING were cultured in T-25 flasks (25 cm2) in DMEM supplemented with 10% heat-inactivated fetal bovine serum, 1× Pen-Strep, and Blasticidin (0.01 mg/mL). At ∼ 80% confluence, cells were treated with UM-232-Al (0.5 μM or 1 μM in DMSO) in FBS-free DMEM for 4 h. Cells were harvested by scraping and centrifuged at 300 × g for 5 min. Pellets were resuspended in lysis buffer (1× PBS containing 1× Halt protease inhibitor and 1% NP-40), sonicated, and protein concentration was determined using the DC Protein Assay (Bio-Rad).

Lysates (2 mg/mL; 50 μL final volume; 100 μg total protein) were subjected to biotinylation via click chemistry using Biotin-N3 (100 μM), freshly prepared TCEP (1 mM), TBTA (0.3 mM), and CuSO4 (4 mM). Reactions were incubated for 1 h at room temperature on a gentle rocker. Proteins were precipitated by centrifugation at 3000 × g for 10 min, resuspended in 1× SDS loading buffer, and boiled for 10 min at 95 °C.

Proteins were resolved by SDS-PAGE (4–20% gel) and transferred to PVDF membranes. Membranes were probed with an anti-STING primary antibody and goat antimouse IRDye 680 secondary antibody. Biotinylated proteins were detected using Streptavidin IRDye 800CW. Dual-labeled bands were visualized using a LI-COR imaging system. All experiments were performed in duplicate.

Pulldown Assay

Cell lysates (2 mg/mL; 50 μL final volume; 100 μg total protein) were biotinylated via click chemistry using Biotin-N3 (100 μM), freshly prepared TCEP (1 mM), TBTA (0.3 mM), and CuSO4 (4 mM). Reactions were incubated on a gentle rocker at room temperature for ∼ 2 h. Precipitated proteins were collected by centrifugation at 3000 × g for 10 min and washed with ice-cold methanol. The dried pellet was resuspended in 30 μL of 1.2% SDS in PBS, diluted to a final SDS concentration of 0.2%, and incubated overnight at 4 °C with 20 μL streptavidin-agarose beads on an end-overend shaker. The following day, samples were incubated at room temperature for 2 h to solubilize any precipitated SDS. Beads were collected by centrifugation at 1300 × g for 3 min and washed sequentially with 2 M urea (2 × 250 μL), PBS (3 × 250 μL), and water (3 × 1 mL), pelleting between washes. Washed beads were resuspended in 30 μL of 1× SDS loading buffer containing 4 M urea, boiled at 95 °C for 15 min, and analyzed by SDS-PAGE (4–20% gel). Proteins were transferred to PVDF membranes and probed with an anti-STING primary antibody and goat antimouse IRDye 680 secondary antibody. Immunoblots were visualized using a LI-COR imaging system. All experiments were performed in duplicate.

Hepatic Microsomal Stability

Test compound (5 μL, 100 μM stock) was added to 445 μL of microsomal buffer and preincubated at 37 °C with shaking (600 rpm) for 15 min. A 45 μL aliquot (0 min) was quenched with 400 μL of ice-cold solution containing tolbutamide and telmisartan (50 ng/mL each). The reaction was initiated by adding 5 μL of 10 mM NADPH to the remaining mixture. For −NADPH controls, buffer was added in place of NADPH and samples were incubated for 45 min prior to quenching. Reactions were incubated at 37 °C (600 rpm), and 50 μL aliquots were collected at 5, 10, 15, 30, and 45 min and quenched with internal standard solution. Samples were vortexed (1000 rpm, 10 min), centrifuged (4000 rpm, 30 min, ∼6 °C), and supernatants were analyzed by LC–MS/MS.

Site Directed Mutagenesis

HEK-293T cells overexpressing wild type or mutant STING (C292A or C309A) were treated with 5 μM UM-232-Al for 1 h. Cell lysates (2 mg/mL, 50 μL final, total 100 μg) were then biotinylated via click-chemistry using Biotin-N3 (100 μM), freshly prepared TCEP (1 mM), TBTA (0.3 mM) and CuSO4 (4 mM). The lysates were then incubated for 2 h on a rocking platform at room temperature, following which the precipitated proteins were collected via centrifugation at 3000g for 10 min and washed ice-cold methanol. Following the wash, the cell pellet was dried at room temperature for 5 min. The dried pellet was resuspended in 1.2% SDS in PBS (30 μL) and was then diluted to a final SDS concentration of 0.2% with PBS and incubated overnight with streptavidin-agarose beads (20 μL) at 4 °C on an end-over end rocker. The following day, the proteins were incubated at room temperature for 2 h. The streptavidin beads were collected by centrifugation at 1,300g for 3 min and were subsequently washed with 2 M urea (2 × 250 μL), PBS (3 × 250 μL), and water (3 × 1 mL). The washed beads were resuspended in 1X SDS loading dye with 4 M urea (30 μL) and boiled at 95 °C for 15 min. The proteins were analyzed by Western blot probed with primary (α-STING) and secondary (goat anti mouse IR dye 680) antibodies. The immunoblotted protein bands were visualized using a LICOR Image Analyzer. All the experiments were performed in triplicate.

RT-qPCR in WT BMDMs

Treated cells were lysed in TRIzol reagent. Total RNA was isolated using the Direct-zol RNA miniprep kit and quantified via Nanodrop ND-1000 spectrophotometer. To produce cDNA, 1 μg of RNA was reverse transcribed using iScript Reverse Transcription Supermix. qPCR analysis was done on 20 ng of cDNA using the iQ SYBR Green supermix reagent. Gene expression was normalized to TATA-binding protein (TBP) expression, and relative mRNA expression was calculated by the change in cycling threshold method as 2–ΔΔC(t). Amplification specificity was assessed via melting curve analysis. Primer sequences are provided in Table S2.

Isolation and Culture of Bone Marrow-Derived Macrophages

Bone marrow was harvested from wild-type C57BL/6 mice by flushing femurs and tibias with complete RPMI medium. The collected marrow cells were cultured in complete RPMI supplemented with 20% (v/v) conditioned medium from L929 mouse fibroblasts. Cultures were maintained at 37 °C in a humidified incubator with 5% CO2 for 4 days, after which the medium was replaced and cells were incubated for an additional 3 days. On day 7, adherent cells were detached and seeded at a density of 1 × 106 cells/mL.

Inhibition of STING Signaling

Following a 24-h resting period, wild-type BMDMs were pretreated with UM-232 (5 μM) for 1 h. Subsequently, cells were stimulated with the STING agonist diABZI-3 (500 nM) for varying durations (0–120 min) prior to lysis.

Immunoblotting

For immunoblot analysis, cells were lysed directly in 1× Laemmli sample buffer. Phosphorylation of signaling proteins was assessed using anti-pTBK1 and anti-pIRF3 antibodies. For native gel analysis of STING oligomerization, cells were lysed in NP-40 lysis buffer (10 mM Tris-HCl pH 7.4, containing 150 mM NaCl, 0.5% (w/v) IgePal, 50 mM NaF, 1 mM Na3VO4, and 1 mM phenylmethylsulfonyl fluoride) supplemented with protease inhibitor. Native fractions were mixed with 1× NativePAGE sample buffer, while reduced fractions were mixed with 1× Laemmli sample buffer. STING oligomers were detected using an anti-STING antibody (Cell Signaling; Cat#13647).

Statistical Analysis

For comparisons of two groups two-tailed students’ t test was performed. Multiple comparison analysis was performed using two-way ANOVA. Mantel-Cox was used for survival analysis. Three to ten mice were used per experiment, sufficient to calculate statistical significance, and in line with similar studies published in the literature.

Safety Statement

No unexpected or unusually high safety hazards were encountered.

Supplementary Material

ml6c00114_si_001.pdf (6.3MB, pdf)

Acknowledgments

The authors gratefully acknowledge Harikesh Kalonia (Syngene International Ltd., Bangalore 560100, India) for conducting mouse and human metabolic studies.

Glossary

Abbreviations

cGAS

cyclic GMP-AMP synthase

STING

Stimulator of Interferon Genes

SAR

structure–activity relationship

cGAMP

2′3′-cyclic GMP-AMP

TBK1

TANK-binding kinase 1

IKK

IκB kinase

IRF3

Interferon regulatory factor 3

IFNβ

Interferon beta

IL6

Interleukin 6

AGS

Aicardi-Goutières syndrome

SLE

systemic lupus erythematosus

SAVI

STING-associated vasculopathy with onset in infancy

ALS

amyotrophic lateral sclerosis

iBMDMs

immortalized bone marrow-derived macrophages

WT

wild-type

CuAAC

copper-catalyzed azide–alkyne cycloaddition reaction

diABZI

linked amido benzimidazole

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00114.

  • Detailed description of the synthesis of the compounds (Schemes S1–S15) as well as comprehensive analytical data, including NMR spectra, HPLC traces, and ESI-MS spectra of the final compounds (Figures S1–S15); dose–response curves for both inhibition and cytotoxicity (Figures S16–17), hepatic microsomal stability results (Table S1) and primers (Table S2). (PDF)

This work was supported in part by National Institutes of Health grants GM118112.

The authors declare the following competing financial interest(s): PRT is a scientific founder of Danger Bio.

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