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. 2025 Aug 1. Online ahead of print. doi: 10.1039/d5md00397k

Hinge binder modification into imidazopyridine for targeting actionable mutations of RET kinase

Arunkranthi Maturi a, Vinay Pogaku a, Surendra Kumar a, Mi-hyun Kim a,✉
PMCID: PMC12434619  PMID: 40959599

Abstract

The RET proto-oncogene is a critical oncogenic driver in the development of several types of cancer. Despite the existence of clinically approved RET inhibitors, their limited response rates and emergence of resistance due to diverse actionable mutations underscore the need for novel therapeutics. Herein, we report substituted imidazo[1,2-a]pyridine derivatives as new RET inhibitors exhibiting IC50 values as low as 11 nM against three distinct point mutations and three important RET fusions. The binding mode and measured potency were elucidated by induced-fit docking simulations and cardiotoxicity was evaluated.

The designed imidazo[1,2-a]pyridines were synthesized to target actionable RET mutations. The best compound exhibited an IC50 of 11 nM against diverse RET alterations. Binding modes with potency were investigated with cardiotoxicity evaluation.graphic file with name d5md00397k-ga.jpg

1. Introduction

Rearranged during transfection (RET) is a receptor tyrosine kinase that activates cell signaling pathways, including PI3K/AKT and MAPK, to lead to cell survival, proliferation, movement, and diversification.1 The phosphorylation and activation of RET protein occur after ligand-independent homodimerization or binding interactions with ligands such as glial cell line-derived neurotrophic factor (GDNF).2 However, RET alterations, such as point mutations, gene fusions, gene loss, missense mutations in specific codons, amplification, and rearrangements, can lead to constitutive RET activation, bypassing these canonical mechanisms. Altered RET proteins have been identified as oncogenic drivers of versatile solid cancers, including non-small cell lung cancer (NSCLC), differentiated thyroid cancer (DTC), papillary thyroid carcinoma (PTC), medullary thyroid cancer (MTC) metastatic, and colorectal cancer (mCRC).3–7 Some of these alterations cause malignant cancers.4–8 For example, a subset of patients with NSCLC harboring RET fusions present with low tumor mutational burden (TMB) and low programmed cell death protein-1 (PD-L1) expression (“cold tumor”), and respond poorly to immunotherapy.9,10 Due to its clinical significance, the NCCN Clinical Practice Guidelines in Oncology have recommended RET as a biomarker for testing in NSCLC.11 While some multi-kinase inhibitors and RET-selective inhibitors are clinically approved for RET-altered cancers, several key questions remain unanswered:

Which actionable mutations are clinically meaningful? Why do some patients exhibit low response rates to RET inhibitors? How can future inhibitor design overcome drug resistance?12 Among the various reported RET alterations, RET-KIF5B is one of the most frequently observed oncogenic fusion genes, accounting for ∼66% of RET fusions in NSCLC.7 In contrast, RET-altered solid tumors other than NSCLC exhibit different fusion partner frequencies, with NCOA4 (32.6%) and CCDC6 (29.9%) predominant.7 Point mutations are significant not only as oncogenic drivers, but also as key determinants of drug resistance. While diverse point mutations have been reported (including gatekeeper, solvent front, gate wall, and P-loop mutations), gatekeeper (V804) and solvent front (G810) mutations have been reported in relation to drug sensitivity and acquired resistance.12–14 Although pralsetinib and selpercatinib (Fig. 1) have clinically demonstrated their superior selectivity and potency over earlier multi-kinase inhibitors,12,15 the development of “ideal” molecular probes remains essential for elucidating the molecular mechanisms underlying actionable RET mutations and designing breakthrough drugs to address these mutations. For example, despite their effectiveness against RETV804M/L (gatekeeper mutation),16 pralsetinib and selpercatinib have presented significant limitations in addressing solvent front mutations and multiple alterations, posing significant clinical challenges. Therefore, we modified the structures of RET hinge binders to overcome actionable RET alterations. To address these limitations, we previously modified the pyrazolopyridine hinge binder scaffold of selpercatinib into imidazopyridazine and introduced extended substituent at the second and sixth positions of the hinge binder (Fig. 1).12 In the present study, we explored the imidazopyridine scaffold, which contains fewer nitrogen atoms than imidazopyridazine. While increased aromatic nitrogen atoms (Naro) in the hinge binder can enhance “kinase-likeness”,17,18 they also increase the hERG binding affinity or metabolic reactivity. To consider drug-likeness and drug efficacy, we selected one nitrogen atom that was neither involved in hydrogen bonding with the hinge region nor essential for facilitating synthetic chemistry. Furthermore, two structural variations of the imidazopyridine core were investigated: R1 substituents at the 6-position and R2 substituents at the 2-position (Fig. 1). We elongated the imidazopyridine hinge binder with several privileged tails (aniline derivative) of known type II kinase inhibitors and compared their effects with that of a less-favoured tail.19,20

Fig. 1. A. This study focused on the imidazole [1,a]pyridine hinge binder for multiple actionable mutations. B. FDA-approved RET selective inhibitors. C. Computationally predicted binding interaction of the designed hinge binder scaffolds.

Fig. 1

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2. Results and discussion

2.1. Established synthetic routes of imidazopyridine derivatives

Compounds 9a–k and 11a–c were synthesized using optimized Scheme 1. The reaction of ethyl 2-bromoacetate under neat conditions yielded compound 5, which was then treated with phosphorus oxychloride (POCl3) to obtain compound 6. Suzuki coupling reactions were then employed to synthesize intermediates 7a–h and 10a–c.21 Iodination of compound 7 produced the key intermediate 8a–h, which was further subjected to Sonogashira coupling to furnish the desired compounds 9a–k.22 Compounds 11a–c were synthesized via alkylation reactions (Scheme 1). The desired products 17a–d, as well as compounds 19 and 20, were synthesized using the elaborated Scheme 2. Cyclization was carried out using ethyl bromopyruvate under heating at 110 °C, yielding compound 13. Subsequently, iodination reaction was performed to produce compound 14b, while 14a was procured.

Scheme 1. Synthesis of compounds 9a–k and 11a–c. Reaction conditions: (a) ethyl 2-bromoacetate, rt, 72.8%. (b) POCl3, 110 °C, 65%. (c) Boronic acids and K2CO3, Pd(dppf)Cl2, 90 °C, 12 h, 60%. (d) NIS, DMF, rt, 56.85%. (e) 18i, 18ii, 18iii, cBRIDP, [(cinnamyl)PdCl]2, Et3N, 2% TPGS/H2O, 45 °C, THF, 51.7%. (f) Pd(dppf)Cl2, K2CO3, 90 °C, 12 h, 60%. (g) 4iv (amine), K2CO3, DMF, 90 °C, 35%.

Scheme 1

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Scheme 2. Synthesis of compounds 17a–d, 19, and 20. Reaction conditions: (a) ethyl bromopyruvate, rt, 60%. (b) NIS, DMF, rt, 55%. (c) THF: MeOH: H2O, rt, 50%. (d) Amine, DIPEA, T3P, CH2Cl2, 45%. (e and f) cBRIDP, [(cinnamyl)PdCl]2, Et3N, 2% TPGS/H2O, THF, 45 °C, 45%. (g) SnCl2, 70 °C, 18%.

Scheme 2

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Hydrolysis of 14a yielded acid 15, which was then coupled with amines via acid–amine coupling to synthesize the key intermediates 16a–c. Finally, Sonogashira coupling was employed to obtain the desired final compounds 17a–d and 19. Compound 20 was synthesized by reducing the nitro group to an amine using tin(ii) chloride (SnCl2).23

2.2. SAR screening of imidazopyridine derivatives

R1 and R2 substituents were expected to be oriented toward the solvent front and gatekeeper region, respectively.12 Therefore, for the systematic structural investigation of the imidazopyridine scaffold, the chloro group was initially fixed at the 2-position to obtain testing compounds with diverse R1 substituents through facile and rapid synthesis (Scheme 1). Systematic modifications of the R1 substituent were performed with privileged tail t1 (of AMN-107),24 resulting in compounds 9a–e, including a chloro substituent (9a), thiophene substituents (9b and 9c), pyrazole (9d), and pyridine (9e). Fig. 2 shows a structural overview of the synthesized 14 compounds 9a–k and 11a–c. RET panel screening at a single concentration demonstrated the preference of a heteroaryl group with a hydrogen-bonding acceptor (e.g., pyridyl group of compound 9e, furan group of compound 9iversus pyrazole group of compound 9d).25 Meanwhile, testing of the four tails presented the scope of this substituent effect. Retaining the pyridine group at the 6-position while changing the tail t2 (compound 9g), resulted in a notable reduction in RET inhibitory activity. Moreover, a fluorine atom was introduced into the aromatic ring of tail t2 to modulate its electronic properties for SAR studies. Fluorine can act as a bioisostere or as part of a bioisosteric group, replacing lone pairs of electrons, hydrogen atoms, or the methyl group, and can also mimic the functional properties of carbonyl, carbinol, and nitrile groups.26 Even if we intended to restrict the conformation through the intramolecular F⋯H–N of the amide group, the pose of compound 9f–g exhibited the trivial contribution of the interaction to desirable bioactive conformation in our molecular docking simulations (Fig. S1–S4). Various R1 substituents were further combined with tail t3, thereby yielding compounds 9h–k, and their inhibitory potencies against RET kinase were assessed. Compounds 11a–c showed dramatically decreased RET inhibitory activities with the simple tail 4 compared with the privileged tails of type II kinase inhibitors (tail 1–3) shown in Fig. 2.19,20 Effective inhibition of the actionable mutant RETV804M encouraged us to further modify this hinge binder. Thus, we replaced the Cl group at the 6-position with the CF3 group and introduced various R2 groups (ester, cyclic tertiary amide, and secondary aryl amide) into the 2-position.27 We expected the CF3 group to be well desolvated near the water front region to enhance the binding affinity with another actionable mutant RETG810R. Regrettably, all design attempts at the 2-position to occupy the small pocket near the gatekeeper residue, including compound 17c benchmarked from the pyrazole amine of pralsetinib,28 failed to demonstrate desirable kinase inhibitory activity (Fig. 3 and S6). Subsequently, with the ester group fixed at the 2-position, we further investigated pharmacophores suitable for the R1 group at the 6-position. The comparable activities of compounds 9h–9k suggested that the size of the R1 group did not make a difference in inhibitory activities. Therefore, evidence encouraged us to introduce a small substituent at the 6-position exploring beyond heteroaryl groups. Additional small R1 groups (–CF3, –NO2, –NH2) could be designed based on the context of priori screening using compounds 9a–k. The NO2 group was introduced at the R1 position instead of the CF3 group, while maintaining the smallest R2 substituent. Encouragingly, this replacement resulted in improved inhibitory activities against every RET panel (compound 17aversus compound 19). Therefore, the highly electron-withdrawing group was replaced with the electron-donating NH2 group to maintain a hydrophilic property near the water front region while increasing the electron density of the bicyclic aromatic ring.29 Compound 20, containing an NH2 group, showed a decreased inhibitory effect for RETG810R but maintained comparable to compound 19 for RETV804M inhibitory activity to compound 19 (Fig. 3 and 4). The inhibitory potency values of compound 19 (–NO2) and 20 (–NH2) also gave additional knowledge: the R1 group at the 6-position could be replaced with any hydrogen acceptor regardless of it being electron-rich or deficient. Based on the SAR study of imidazopyridine derivatives, several promising compounds were selected for further testing against RET fusion mutations. Notably, compound 20 was the most active inhibitor for each RET fusion (Fig. 4).30

Fig. 2. A. Imidazopyridine derivatives with four types of tails exploring substituents directed towards R1. B. Percent residual activity of the designed compounds at 1 μM concentration (exception compound 9g: 0.1 μM) with RET kinases RET (green), G810R (blue), and V804M (red). Each activity value is shown in Table S1.

Fig. 2

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Fig. 3. A. Imidazopyridine derivatives with diverse substituents with tail t317a–d and optimization of compound 19 and 20. B. Percent inhibition of tested compounds against RET (green), G810R (blue), and V804M (red). Testing concentration at 1 μM (except compound 20: 0.1 μM). Each activity value is shown in Table S1.

Fig. 3

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Fig. 4. A. Exploration of the R1 group using chosen compounds. B. Percent inhibition activity against RET fusions RET-CCDC6 (yellow), RET-NCOA4 (magenta), and RET-KIF5B (brick red). Each activity value is shown in Table S2. Testing concentration at 1 μM.

Fig. 4

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2.3. Developability of imidazopyridine derivatives

Based on preliminary screening results, we further investigated the imidazopyridine scaffold by evaluating selected promising derivatives for their inhibitory potencies (IC50) against representative actionable RET mutants (RETG810R and RETV804M). Compound 9e demonstrated moderate inhibitory potency of 0.8 μM against the gatekeeper mutant (RETV804M) but exhibited limited potency against the solvent front mutant (RETG810R) (Table 1). In contrast, compounds 9i–k and 20 showed enhanced potency, displaying approximately two- to three-fold improvements over the RETV804M mutant (Table 2).

Table 1. Enzyme inhibition (IC50) against RETV804M and RETG810R (μM).

graphic file with name d5md00397k-u1.jpg
Entry R1 R2 R4 Kinase assay IC50 (μM)
RETV804M RETG810R
9e graphic file with name d5md00397k-u2.jpg Cl graphic file with name d5md00397k-u3.jpg 0.800 >10
9h graphic file with name d5md00397k-u4.jpg Cl graphic file with name d5md00397k-u5.jpg 0.011 1.34
9i graphic file with name d5md00397k-u6.jpg Cl 0.024 3.11
9j graphic file with name d5md00397k-u7.jpg Cl 0.017 1.69
9k graphic file with name d5md00397k-u8.jpg Cl 0.028 >10
19 NO2 CO2Et 0.044 7.80
20 NH2 CO2Et 0.028 0.96
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Table 2. Assessment of therapeutic index of representative RET kinase inhibitors against hERG toxicity.

graphic file with name d5md00397k-u9.jpg
Entry Therapeutic ratio IC50 (hERG)/IC50 (RETV804M) Therapeutic ratio for IC50 (hERG)/IC50 (RETG810R)
9e 37.50 3.00
9h 363.63 2.98
9i 174.16 1.34
9j 481.17 4.84
9k 142.85 <1.0
19 60.90 <1.0
20 167.85 4.89
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Notably, compound 20 exhibited significant enhancement, demonstrating up to a ten-fold increase in potency against the RETG810R solvent front mutation. Structurally, these potent derivatives commonly featured electron-rich substituents and hydrogen bond-acceptor atoms at the 6-position: a furan group in compound 9i, a pyrimidine group in compound 9j, and a benzodioxole moiety in compound 9k. Interestingly, despite the contrasting electronic features of R1 substituents at this position, compound 19 containing the electron-withdrawing group maintained comparable potency with electron-rich analogs. These results suggested that a hydrogen bond-acceptor at the 6-position conferred advantageous interactions against the gatekeeper mutation.25 However, this beneficial effect was not maintained in the solvent front RETG810R mutant (Table 1).31

For further evaluation of our test compounds, therapeutic ratios were determined to evaluate the safety profiles and guide future optimization of these imidazopyridine derivatives.32 Compounds 9e, 9i, 9j, 9k, 19 and 20 demonstrated highly favorable therapeutic ratios against RETV804M, indicating substantial potential for further development. For RETG810R, the therapeutic ratios were relatively modest, indicating that further optimization was needed to improve safety margins.32 These findings provide valuable insights into the SAR of this imidazopyridine series, emphasizing the importance of carefully balancing kinase targeting with hERG anti-targeting to mitigate off-target toxicity.33 Each experiment demonstrated that compound 20 was the best compound among the imidazopyridine series. Finally, the anti-proliferative effect of compound 20 was further tested under NSCLC (Lc/2d cell lines having RET-CCDC6 fusion) to give an IC50 of 5.3 μM (Fig. 5D). This double confirmation through the standard Cell Titer-Glo without optimization of assay conditions suggested the biochemical potency of compound 20, and showed the potential for future drug discovery for RET alterations.34

Fig. 5. Molecular docking simulation of compound 20 along with potency measurement against additional RET alterations. A. Best docking pose for RETV804M. B. Best docking pose for RETG810R. C. Best docking pose for RETI788N. D. Experimentally measured IC50 of compound 20 for the additional four RET alterations along with cell-based assay. Compound 20 (green), key amino acid residues (yellow), and hydrogen bond interactions (black dashed lines).

Fig. 5

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2.4. Mode of action and kinase selectivity of the best compound

The best compound 20 was further examined for its binding mode and additional RET alterations, such as RETI788N (Fig. 5).35,36 Using induced-fit molecular docking simulation, we explored the binding poses and key molecular interactions of compound 20 within the active site of RET kinase (modified RET using PDB ID: 7JU6). In the RETV804M mutant, compound 20 effectively engaged the hinge residue A807 and formed critical hydrogen bonds between its amide group and D892. Additionally, the piperazine tail contributed to binding stabilization by interacting with E768. In the RETG810R mutation, the compound retained a similar orientation at the hinge region, with the amine substituent at the 6-position of the imidazopyridine core forming a key interaction with L730, whereas the tail amide continued to engage D892. Likewise, in the RETI788N mutant, compound 20 maintained hydrogen bonding with A807 via the imidazopyridine nitrogen, and the mutated asparagine residue (I788N) interacted with the carbonyl moiety. Across all mutants, the tail amide consistently served as a critical anchor point through hydrogen bonding with D892. These in silico results were consistent with the in vitro experimental data. Clearly, compound 20 exhibited superior potency against RETV804M than the potencies against other point mutants (IC50 of RETV804M: 28 nM vs. IC50 of RETG810R: 0.96 μM, RETI788N: 1.06 μM), and the distance from A807 also supported the experimental difference (RETV804M: 2.27 vs. RETG810R and RETI788N: 2.55–2.56 Å). In the best poses, RETV804M allowed the favorable accommodation of the ester substituent at the R2 position within the altered binding pocket upon close interaction with the hinge region. Meanwhile, it seems that RETG810R and RETI788N could not retain the close interaction with the hinge region as much as RETV804M because of the mutated bulky and polar arginine or asparagine side chains. Moreover, although we expected spatial compatibility between the R810 residue and amine group of compound 20, they were quite distant. Despite the hydrogen bond with N788, the combined summation of non-covalent interactions with compound 20 gave 2.56 Å as a suitable distance from the hinge region of the RETI788N mutation, which altered the structure of the αC-helix—an essential component for kinase activity and inhibitor binding.37 These docking results suggested that the benefit from the R2 substituent could not be retained in these point mutations. Finally, we measured the inhibitory potencies of compound 20 against the three most important RET fusion proteins: CCDC6, KIF5B, and NCOA4. Despite the unknown 3D structure of the RET fusion proteins, compound 20 demonstrated nanomolar potency for each fusion protein (Fig. 5D). These findings suggested that this scaffold holds potential and may serve as a useful probe molecule for future mechanistic investigations of RET alterations.38

3. Conclusions

A series of imidazopyridine-based RET kinase inhibitors were designed and optimized to enhance drug safety and therapeutic potential. Strategic structural modifications involved the incorporation of diverse R1 groups at the 6-position and R2-group introduction of cyclic tertiary, secondary aryl amides and ester at the 2-position, in combination with four known tail groups. For SAR optimization, investigation of the R1 group, comparing heteroaryl groups, cyclic alkyl group, and halogen group revealed stereoelectronic and polarity patterns at the 6-position. In particular, the comparable activities of compounds 9h–9k suggested further pharmacophore investigation among small R1 groups to optimize the potency for RET alterations. While the 6-pyridine substituent emerged as the most favorable in terms of hERG safety profile, compound 20 demonstrated the superiority to others across multiple RET alterations and therapeutic ratio. Molecular docking further supported the observed inhibitory activity by revealing the interaction distance with the hinge region within the ATP-binding site of RET kinase. In the recent future, the molecular mechanistic studies on RET fusion alterations are expected using this promising novel tool compound.

Author contributions

MHK conceived and designed the study and received research funding. AM synthesized the compounds using the drug scaffold design of MHK. MHK, AM, VP, and SK designed the bioassay, conducted computational modeling, and analyzed the final data. MHK and AM wrote the manuscript, and MHK, AM, and VP revised it. MHK provided the molecular modelling laboratory and in vitro research facility. All authors approved the final version of the manuscript.

Conflicts of interest

All other authors declare no conflicts of interest.

Supplementary Material

MD-OLF-D5MD00397K-s001

Acknowledgments

This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (2022R1A2C2091810). This research was also supported by a grant from the Korea Machine Learning Ledger Orchestration for Drug Discovery Project (K-MELLODDY), funded by the (RS-2024-00450691). GL-Project of Gachon University research fund of 2021 also supported this research (GCU-202106240001). The authors greatly appreciate Professor Sung-Min Ahn and Immunoforge for their valuable comments on RET drug discovery.

Data availability

Data for this study, including the procedures for chemical compounds, their spectra and their bioassay data, are available in the SI (submitted as a DOCX file). See DOI: https://doi.org/10.1039/D5MD00397K.

The data supporting the conclusions reached from our study have been included as part of the SI.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

MD-OLF-D5MD00397K-s001
MD-OLF-D5MD00397K-s001.pdf (5.1MB, pdf)

Data Availability Statement

Data for this study, including the procedures for chemical compounds, their spectra and their bioassay data, are available in the SI (submitted as a DOCX file). See DOI: https://doi.org/10.1039/D5MD00397K.

The data supporting the conclusions reached from our study have been included as part of the SI.

Articles from RSC Medicinal Chemistry are provided here courtesy of Royal Society of Chemistry

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