Development of a Novel Tropomyosin Receptor Kinase Inhibitor Based on Structure–Activity Relationships: Identification of a Promising Clinical Candidate

Abstract

Tropomyosin receptor kinase (TRK) inhibitors have emerged as promising therapeutic agents for various cancers. In this study, we report the discovery and characterization of CH7070868, a novel and potent TRK-selective inhibitor. Through structure–activity relationship studies, we optimized the lead compound (CH7057288) to achieve superior TRK inhibition while reducing the risk of drug–drug interactions (CYP3A4 induction). CH7070868 demonstrated high selectivity for TRK over other kinases (KDR and LCK) and exhibited potent inhibitory activity in both biochemical and cellular assays. Our findings suggest that CH7070868 represents a promising candidate for further development as a next-generation TRK inhibitor with an enhanced efficacy.

The neurotropic tyrosine receptor kinase (NTRK) gene family, comprising NTRK1, NTRK2, and NTRK3, encodes the tropomyosin receptor kinases TRKA, TRKB, and TRKC, respectively. These isotypes share over 70% sequence homology in their kinase domains. In 2013, Doebele et al. identified NTRK rearrangements, such as MPRIP-NTRK1 and TPM3-NTRK1, as oncogenic drivers in a subset of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cases.[1] NTRK1 fusions in NSCLC are mutually exclusive with other known oncogenic driver mutations, including KRAS, EGFR, and ALK.[2] Subsequently, oncogenic rearrangements involving NTRK2 and NTRK3 were also discovered.[3]

The clinical significance of these findings led to the development of targeted therapies. In 2018 and 2019, the U.S. Food and Drug Administration (FDA) approved larotrectinib and entrectinib, respectively, for the treatment of TRK-positive cancers.[4] Furthermore, several TRK inhibitors entered the clinical stage (Figure [1]).[5] Previously, we reported the discovery of the clinical candidate CH7057288, which demonstrated oral efficacy in mouse xenograft models expressing NIH3T3 MPRIP-NTRK1.[6]

Building upon the excellent in vivo efficacy of CH7057288 (1), we explored opportunities to further enhance its activity. Utilizing structure-based drug design (SBDD) and conducting a structure–activity relationship (SAR) study focused on the γ-position of the pyridine ring and the 8-position side chain, we successfully developed the novel, potent, and selective pan-TRK inhibitor CH7070868. This compound demonstrated superior TRK inhibitory activity and more potent antiproliferative effects against NIH3T3 MPRIP-NTRK1 cells compared to CH7057288 (1). This advancement represents a significant step forward in our ongoing efforts to develop more effective targeted therapies for TRK-positive cancers.

We previously reported that the lead compound 1 demonstrated high TRK selectivity and potent antitumor effects with low risk of CYP3A4 induction.[6] Recognizing that enhancing antitumor efficacy while maintaining high TRK selectivity could provide a more valuable therapeutic option in clinical settings, we sought to enhance antitumor efficacy by optimizing TRK inhibitory and antiproliferative activities while minimizing CYP3A4 induction to reduce potential drug–drug interactions. The FDA and EMA guidelines recommended mRNA-based CYP induction risk assessment, but its low throughput limits large-scale screening.[7] [8] High-throughput enzymatic oxidation assays were thus adopted, enabling efficient compound screening and SAR construction for CYP3A4 induction. Kuramoto et al. reported a strong correlation between enzymatic oxidation activity and mRNA expression level, validating this rapid risk assessment for drug discovery.[9]

This study was undertaken to optimize 1, with the goal of developing a more efficacious TRK inhibitor that could potentially offer improved clinical outcomes. We hypothesized that subtle structural modifications could lead to compounds with increased potency against TRK and enhanced antiproliferative activity, while preserving the favorable TRK selectivity profile of the parent compound. To this end, we embarked on a systematic SAR study, focusing on key regions of the molecule that our molecular modeling studies suggested might impact TRK inhibition and antiproliferative activity. The results of this investigation and their implications for the design of next-generation TRK inhibitors are presented herein.

Crystallographic analysis of 1 bound to TRKA (PDB code: 5WR7) reveals hydrogen bonding with the backbone amide of Met592 in the hinge region, and CH–π interactions with L516, V524, and A542. Given the high sequence homology (>70%) among TRKA, B, and C kinase domains, with L516 and V524 conserved across all three isoforms, and A542 maintained in TRKA and TRKC (replaced by serine in TRKB). Many amino acid residues in the back pocket region and near the 8-position side chain are also conserved among these isoforms. Consequently, our compounds are likely to exhibit pan-TRK inhibition despite side chain modifications. Therefore, we discussed TRKA inhibition as a representative model for pan-TRK activity (Figure [2]). The co-crystal structure revealed that modifying the amide group at the γ-position of the pyridine ring could potentially improve TRKA inhibitory activity by effectively occupying a lipophilic pocket. Based on this insight, we explored the impact of various amide group modifications on TRKA inhibitory activity and antiproliferative effects.

We examined the impact of length and bulkiness of substituents on TRKA inhibitory activity and antiproliferative activity against NIH3T3 MPRIP-NTRK1 (Table [1]). We first investigated the SAR for the length of alkyl substituents. TRKA inhibition increased from Me to Et and n-Pr but decreased with longer chains (n-Bu; 2a–d). Bulky neopentyl group (2e) led to reduced TRKA inhibition, suggesting limited space in the lipophilic pocket. While the i-Pr group (2f) showed improved TRKA inhibition by 2-fold compared to 1, the antiproliferative activity was weaker than that of 1. Various tertiary alkyl groups other than the tert-butyl group were investigated, but only the 1-methylcyclopropyl group (2g) exhibited 2-fold improved TRKA inhibitory activity compared to 1, yet did not improve antiproliferative activity. The discrepancy between the TRKA inhibitory activity and the antiproliferative activity is suspected to be due to decreased membrane permeability. However, this chemical series exhibited low solubility in a standard cell membrane permeability test (e.g., CaCO-2, PAMPA assay) due to high lipophilicity, precluding precise measurement of cell membrane permeability. The significant reduction in TRKA inhibitory activity observed with dimethylamide group (2h) revealed the importance of the amide NH for TRKA inhibition, although no clear interaction with TRKA was detected in the co-crystal structure (Figure [2]). Although several compounds indicated improved TRKA inhibitory activity by obtaining interactions with the lipophilic pocket of TRKA, a corresponding enhancement in antiproliferative activity was not observed. The results from this series of derivatizations demonstrated that the t-Bu group (1) remains the optimal substituent in terms of antiproliferative activity.

Table 1 Structure–Activity Relationship of γ-Amide at the Pyridine Ring

Next, we aimed to establish an SAR for TRKA inhibitory activity, antiproliferative activity, and CYP3A4 induction potential with respect to the 8-position side chain (Table [2]). The co-crystal structure of TRKA and 1 (Figure [2]) revealed that the 8-position extends from the binding pocket to the solvent-accessible region, suggesting that various substituents could be introduced at this position. This observation was further supported by our previously reported results on the derivatization of the 8-position, which demonstrated the feasibility of incorporating diverse substituents. Previous SAR studies have indicated that the introduction of a sulfonamide group at the 8-position tends to mitigate CYP3A4 induction.[6] Given the high potential of the methanesulfonamide group to avoid CYP3A4 induction, we explored the alkyl group while maintaining the sulfonamide moiety. Our aim was to investigate how these alterations would affect TRKA inhibitory activity, potentially allowing us to optimize both CYP3A4 induction avoidance and TRKA inhibition simultaneously. The ethyl group (3a) exhibited approximately 2-fold improvement in TRKA inhibitory activity compared to 1, along with enhanced antiproliferative activity against NIH3T3 MPRIP-NTRK1 cells. Longer carbon chain substituents such as n-propyl (3b) and n-butyl (3c) groups showed diminished TRKA inhibitory activity compared to the ethyl group (3a). Similarly, branched alkyl groups, including i-Pr and c-Pr (3d and 3e, respectively), demonstrated reduced TRKA inhibitory potency compared to 3a. While Figure [2] indicated that there appeared to be occupiable space in the vicinity of the 8-methanesulfonamide group, alkyl groups larger than ethyl were not well tolerated. This may be due to the hydrophilic nature of the solvent accessible region. Contrary to our initial expectations, the binding pocket exhibited limited accommodation for lipophilic substituents. The acceptance of lipophilic substituents was more restricted than we had initially anticipated based on the structural analysis. On the other hand, compound 3f, having a hydroxyl group at the terminus of the n-propyl chain, exhibited improved TRKA inhibitory activity and antiproliferative activity against NIH3T3 MPRIP-NTRK1 compared to the n-propyl analogue 3b. The docking model of 3f with TRKA (Figure [3]) reveals that while H594 is positioned in proximity to the hydroxyl group, the distance observed in the docking model was 3.8 Å, indicating that a clear hydrogen bond was not confirmed. This spatial arrangement suggests the potential for enhanced TRKA inhibitory activity through the acquisition of interactions with H594. However, it is noteworthy that this region is situated within the solvent accessible region. Consequently, this environment may prove favorable for the hydrophilic hydroxyl group, potentially explaining its preferred orientation and contribution to the compound’s activity. The interplay between the hydroxyl group, H594, and the solvent accessible region underscores the complexity of protein–ligand interactions and highlights the importance of considering both direct protein contacts and solvent effects. This interpretation represents one possible explanation for the observed effects, although further investigation would be necessary to confirm these hypotheses. Compounds 3a–e maintained low CYP3A4 induction activity (CYP3A4 relative induction, % of rifampicin) similar to 1. However, compound 3f showed 3-fold increase in CYP3A4 relative induction (7% → 22%). Although CYP3A4 induction risk was observed for 3f, it was considered possible to modulate CYP3A4 induction potential through the modification of the 8-position side chain, as seen with compounds 3d,e. Therefore, we decided to investigate whether it was feasible to reduce the elevated CYP3A4 induction potential observed with 3f while simultaneously enhancing TRKA inhibitory activity and antiproliferative effects through further modifications of the 8-position side chain.

Table 2 Structure–Activity Relationship and CYP3A4 Induction for 8-Sulfonamide Analogues

^a The ratio of the compound to DMSO (negative control). Compound concentration was 1.0 μM.

^b The ratio of the compound to rifampicin (positive control, 10 μM). Compound concentration was 1.0 μM.

We investigated the effects of introducing alcohol side chains at the 8-position on TRKA inhibitory activity and CYP3A4 induction activity (Table [3]). Compounds 4a and 4b, bearing diol structures, exhibited TRKA inhibitory activity and antiproliferative activity against NIH3T3 MPRIP-NTRK1 cells comparable to 3f. Interestingly, while 4a, with the R-configuration of the 2-hydroxyl group in the diol side chain, maintained relatively high CYP3A4-inducing activity (20%), 4b, with the S-configuration, showed a significant reduction in CYP3A4 relative induction (5%). This marked influence of hydroxyl group stereochemistry on CYP3A4 induction prompted us to synthesize triol side chain derivatives. Compounds 4c and 4d, having triol side chains, demonstrated negligible CYP3A4 induction (11% and 10%, respectively). Moreover, they exhibited improved antiproliferative activity against NIH 3T3 MPRIP-NTRK1 cells compared to 3f, with 4c showing an approximately 10-fold increase in potency. While the exact mechanism for this enhancement remains unclear, it is possible that 4c may have significantly improved cell membrane permeability. However, a definitive conclusion cannot be drawn due to the limited ability to precisely measure membrane permeability. The significant impact of introducing hydroxyl groups at the 8-position side chain, located in the solvent-exposed region, on antiproliferative activity prompted us to investigate combinations with various amine-containing linkers. Compounds 4e and 4f, featuring piperazine as a linker with terminal diol side chains, exhibited enhanced antiproliferative activity compared to compounds 4a and 4b, which possess only diol side chains. Notably, 4e demonstrated potent antiproliferative activity against NIH3T3 MPRIP-NTRK1 cells with an IC₅₀ of <0.3 nM. However, the piperazine-linked 4e showed a CYP3A4 relative induction exceeding 20%, indicating this compound had a potential CYP3A4 induction risk. Anticipating improved antiproliferative activity by incorporating amine linkers with hydroxy groups, we explored various linkers beyond piperazine. For example, 4g with a pyrrolidine linker showed reduced CYP3A4 induction compared to 3f but did not improve antiproliferative activity. These investigations led to the identification of 4c, which successfully maintained CYP3A4 relative induction below 20% while exhibiting potent antiproliferative activity. This compound represents a significant advancement in our efforts to develop TRKA inhibitors with high TRK selectivity and improved antiproliferative activity.

Table 3 Structure–Activity Relationship and CYP3A4 Induction for 8-Substituted Analogues

^a The ratio of the compound to DMSO (negative control). Compound concentration was 1.0 μM.

^b The ratio of the compound to rifampicin (positive control, 10 μM). Compound concentration was 1.0 μM.

In medicinal chemistry, the focus is on setting up synthetic routes suitable for efficient SAR construction. In this case, we set 3-bromo-8-hydroxy-6,6-dimethylnaphtho[2,3-b]benzofuran-11(6H)-one (5) as a versatile intermediate to efficiently construct SAR for the γ- and 8-position substituents (Scheme [1]).

Based on the synthetic routes shown in Scheme [1], we carried out the synthesis of γ- and 8-substituted derivatives. The synthesis of γ-substituted derivatives is described in Scheme [2]. Compound 6 was synthesized from compound 5 according to a reported procedure.[6] The sila-Sonogashira coupling of 6 with 2-chloro-6-methylisonicotinic acid afforded 7. Compounds 2a–h were prepared by condensation of 7 with the corresponding amines.

The synthesis of 8-substituted derivatives from intermediate 5 is described in Schemes 3 and 4. The TMS-protected ethynylpyridine underwent sila-Sonogashira coupling with 5 to give 8. Compound 8 was treated with 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide to afford triflate 9. Compound 9 was subjected to Buchwald–Hartwig cross-coupling conditions with tert-butyl carbamate, followed by treatment with TMSCl and TFE to afford 10. Cross-coupling of 9 with corresponding sulfonamides provided 3a,d,e (Scheme [3]) Compounds 3b,c,f were synthesized via sulfonation of 10. O-Alkylation of 8 with corresponding tosylates followed by deprotection of acetonide gave 8-diol derivatives 4a,b and 8-triol derivatives 4c,d (Scheme [4]) Compounds 4g and 11 were obtained via S_NAr reaction of 9 with (R)-pyrrolidin-3-ol and piperazine, respectively. Compounds 4e and 4f were synthesized from 11 using the same protocol as in the synthesis of 4a and 4b.

Through the chemical modification of our reported clinical candidate CH7057288, we aimed to improve TRKA inhibitory activity and antiproliferative activity against NIH3T3 MPRIP-NTRK1 while maintaining low CYP3A4 induction potential. Detailed SAR studies at the γ-position of the pyridine ring revealed that a tert-butyl amide group was the optimal substituent. Furthermore, derivatization of the 8-position side chain led to the identification of a hydroxyl group as a crucial moiety for enhancing TRKA inhibitory activity and cell growth inhibition against NIH3T3 MPRIP-NTRK1, while preserving low CYP3A4 induction potential. Notably, among various modifications made at the γ- and 8-positions, the compounds consistently exhibited low potency toward KDR and LCK, which highlights the high selectivity of this series of compounds for the TRK family. This combination of features resulted in compounds with enhanced TRKA inhibition, improved cellular potency, and maintained high TRK selectivity. Consequently, we discovered 4c (CH7070868), which demonstrated over 20-fold improvement in cell growth inhibition activity compared to 1, while maintaining high TRK selectivity and low CYP3A4 induction potential. With its enhanced cell growth inhibition activity, CH7070868 is expected to exhibit more potent in vivo efficacy than CH7057288 in mouse xenograft models with NIH3T3 MPRIP-NTRK1 implantation. CH7070868 is anticipated to provide a new therapeutic option for the treatment of cancer in TRK fusion-positive patients and may serve as a valuable in vitro and in vivo tool for the development of future therapies targeting TRK fusion-positive cancers.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Y. Ono for helpful discussion; Y. Tachibana, K. Sakata, and T. Fujii for biological assays; A. Higashida for CYP induction assays; and M. Arai for mass spectrometry measurements.

• References and Notes

• 1 Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, Mahale S, Davies KD, Aisner DL, Pilling AB, Berge EM, Kim J, Sasaki H, Park S, Kryukov G, Garraway LA, Hammerman PS, Haas J, Andrews SW, Lipson D, Stephens PJ, Miller VA, Varella-Garcia M, Jänne PA, Doebele RC. Nat. Med. 2013; 19: 1469
  PubMedSearch in Google Scholar
• 2 Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. Nat. Commun. 2014; 5: 4846
  PubMedSearch in Google Scholar
• 3a Jones DT. W, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz H.-J, Zichner T, Lambert SR, Ryzhova M, Quang DA. K, Fontebasso AM, Stütz AM, Hutter S, Zuckermann M, Sturm D, Gronych J, Lasitschka B, Schmidt S, Seker-Cin H, Witt H, Sultan M, Ralser M, Northcott PA, Hovestadt V, Bender S, Pfaff E, Stark S, Faury D, Schwartzentruber J, Majewski J, Weber UD, Zapatka M, Raeder B, Schlesner M, Worth CL, Bartholomae CC, von Kalle C, Imbusch CD, Radomski S, Lawerenz C, van Sluis P, Koster J, Volckmann R, Versteeg R, Lehrach H, Monoranu C, Winkler B, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, Ebinger M, Schuhmann M, Cho Y.-J, Pomeroy SL, von Deimling A, Witt O, Taylor MD, Wolf S, Karajannis MA, Eberhart CG, Scheurlen W, Hasselblatt M, Ligon KL, Kieran MW, Korbel JO, Yaspo M.-L, Brors B, Felsberg J, Reifenberger G, Collins VP, Jabado N, Eils R, Lichter P, Pfister SM. Nat. Genet. 2013; 45: 927
  PubMedSearch in Google Scholar
• 3b Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH. B. Cancer Cell 2002; 2: 367
  PubMedSearch in Google Scholar
• 4a Bailey JJ, Jaworski C, Tung D, Wängler C, Wängler B, Schirrmacher R. Expert Opin. Ther. Pat. 2020; 30: 325
  PubMedSearch in Google Scholar
• 4b Yan E, Rajiv Lakkaniga N, Carlomagno F, Santoro M, McDonald NQ, Lv F, Gunaganti N, Frett B, Li H.-Y. J. Med. Chem. 2019; 62: 1731
  PubMedSearch in Google Scholar
• 4c Menichincheri M, Ardini E, Magnaghi P, Avanzi N, Banfi P, Bossi R, Buffa L, Canevari G, Ceriani L, Colombo M, Corti L, Donati D, Fasolini M, Felder E, Fiorelli C, Fiorentini F, Galvani A, Isacchi A, Lombardi Borgia A, Marchionni C, Nesi M, Orrenius C, Panzeri A, Pesenti E, Rusconi L, Saccardo MB, Vanotti E, Perrone E, Orsini P. J. Med. Chem. 2016; 59: 3392
  PubMedSearch in Google Scholar
• 5 Laetsch TW, Hong DS. Clinical Cancer Research 2021; 27: 4974
  PubMedSearch in Google Scholar
• 6 Ito T, Kinoshita K, Tomizawa M, Shinohara S, Nishii H, Matsushita M, Hattori K, Kohchi Y, Kohchi M, Hayase T, Watanabe F, Hasegawa K, Tanaka H, Kuramoto S, Takanashi K, Oikawa N. J. Med. Chem. 2022; 65: 12427
  PubMedSearch in Google Scholar
• 7 FDA guidance for industry, in vitro drug interaction studies – cytochrome P450 enzyme- and transporter-mediated drug interactions (accessed January 6, 2025): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m12-drug-interaction-studies
• 8 Guideline on the investigation of drug interactions. European Medicines Agency; London: 2012. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions-revision-1_en.pdf
  Search in Google Scholar
• 9 Kuramoto S, Kato M, Shindoh H, Kaneko A, Ishigai M, Miyauchi S. Drug Metab. Dispos. 2017; 45: 1139
  PubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 21 January 2025

Accepted after revision: 05 March 2025

Accepted Manuscript online:
05 March 2025

Article published online:
15 April 2025

© 2025. Thieme. All rights reserved

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• References and Notes

• 1 Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, Mahale S, Davies KD, Aisner DL, Pilling AB, Berge EM, Kim J, Sasaki H, Park S, Kryukov G, Garraway LA, Hammerman PS, Haas J, Andrews SW, Lipson D, Stephens PJ, Miller VA, Varella-Garcia M, Jänne PA, Doebele RC. Nat. Med. 2013; 19: 1469
  PubMedSearch in Google Scholar
• 2 Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. Nat. Commun. 2014; 5: 4846
  PubMedSearch in Google Scholar
• 3a Jones DT. W, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz H.-J, Zichner T, Lambert SR, Ryzhova M, Quang DA. K, Fontebasso AM, Stütz AM, Hutter S, Zuckermann M, Sturm D, Gronych J, Lasitschka B, Schmidt S, Seker-Cin H, Witt H, Sultan M, Ralser M, Northcott PA, Hovestadt V, Bender S, Pfaff E, Stark S, Faury D, Schwartzentruber J, Majewski J, Weber UD, Zapatka M, Raeder B, Schlesner M, Worth CL, Bartholomae CC, von Kalle C, Imbusch CD, Radomski S, Lawerenz C, van Sluis P, Koster J, Volckmann R, Versteeg R, Lehrach H, Monoranu C, Winkler B, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, Ebinger M, Schuhmann M, Cho Y.-J, Pomeroy SL, von Deimling A, Witt O, Taylor MD, Wolf S, Karajannis MA, Eberhart CG, Scheurlen W, Hasselblatt M, Ligon KL, Kieran MW, Korbel JO, Yaspo M.-L, Brors B, Felsberg J, Reifenberger G, Collins VP, Jabado N, Eils R, Lichter P, Pfister SM. Nat. Genet. 2013; 45: 927
  PubMedSearch in Google Scholar
• 3b Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH. B. Cancer Cell 2002; 2: 367
  PubMedSearch in Google Scholar
• 4a Bailey JJ, Jaworski C, Tung D, Wängler C, Wängler B, Schirrmacher R. Expert Opin. Ther. Pat. 2020; 30: 325
  PubMedSearch in Google Scholar
• 4b Yan E, Rajiv Lakkaniga N, Carlomagno F, Santoro M, McDonald NQ, Lv F, Gunaganti N, Frett B, Li H.-Y. J. Med. Chem. 2019; 62: 1731
  PubMedSearch in Google Scholar
• 4c Menichincheri M, Ardini E, Magnaghi P, Avanzi N, Banfi P, Bossi R, Buffa L, Canevari G, Ceriani L, Colombo M, Corti L, Donati D, Fasolini M, Felder E, Fiorelli C, Fiorentini F, Galvani A, Isacchi A, Lombardi Borgia A, Marchionni C, Nesi M, Orrenius C, Panzeri A, Pesenti E, Rusconi L, Saccardo MB, Vanotti E, Perrone E, Orsini P. J. Med. Chem. 2016; 59: 3392
  PubMedSearch in Google Scholar
• 5 Laetsch TW, Hong DS. Clinical Cancer Research 2021; 27: 4974
  PubMedSearch in Google Scholar
• 6 Ito T, Kinoshita K, Tomizawa M, Shinohara S, Nishii H, Matsushita M, Hattori K, Kohchi Y, Kohchi M, Hayase T, Watanabe F, Hasegawa K, Tanaka H, Kuramoto S, Takanashi K, Oikawa N. J. Med. Chem. 2022; 65: 12427
  PubMedSearch in Google Scholar
• 7 FDA guidance for industry, in vitro drug interaction studies – cytochrome P450 enzyme- and transporter-mediated drug interactions (accessed January 6, 2025): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m12-drug-interaction-studies
• 8 Guideline on the investigation of drug interactions. European Medicines Agency; London: 2012. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions-revision-1_en.pdf
  Search in Google Scholar
• 9 Kuramoto S, Kato M, Shindoh H, Kaneko A, Ishigai M, Miyauchi S. Drug Metab. Dispos. 2017; 45: 1139
  PubMedSearch in Google Scholar

• Supplementary Material