Resatorvid Explained

Resatorvid (TAK-242) is a cyclohexane derivative that was invented by scientists at Takeda in a drug discovery campaign to identify inhibitors of the receptor TLR4.^[1] It binds directly to cysteine residue 747^[1] intracellularly, preventing TLR4 binding with TIRAP and thus preventing downstream signal transduction.^[2]

A randomized, double-blinded Phase III trial of resatorvid in sepsis was halted early due to lack of efficacy, and the compound has become a widely used tool compound in biological research.^[1]

It has antiinflammatory and neuroprotective effects in preclinical models.^[3] It has been explored in preclinical studies of several forms of cancer, including multiple myeloma, breast cancer, and ovarian cancer,^[4] and has been suggested for study in skin cancers.^[5]

Efforts have been made to improve resatorvid by making prodrugs and deuterated derivatives.

See also

• M62812
• TLR4-IN-C34

Further reading

• Matsunaga N, Tsuchimori N, Matsumoto T, Ii M . TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules . Molecular Pharmacology . 79 . 1 . 34–41 . January 2011 . 20881006 . 10.1124/mol.110.068064 . 7818996 .
• Samarpita S, Kim JY, Rasool MK, Kim KS . Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug . Arthritis Research & Therapy . 22 . 1 . 16 . January 2020 . 31973752 . 6979396 . 10.1186/s13075-020-2097-2 . free .
• Feng Y, Gao J, Cui Y, Li M, Li R, Cui C, Cui J . Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway . Cellular and Molecular Neurobiology . 37 . 1 . 155–168 . January 2017 . 26961544 . 10.1007/s10571-016-0356-1 . 21583205 .
• Dickinson SE, Wondrak GT . TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis . Current Medicinal Chemistry . 25 . 40 . 5487–5502 . 2019 . 28847267 . 10.2174/0929867324666170828125328 . 670318 .
• Kashani B, Zandi Z, Karimzadeh MR, Bashash D, Nasrollahzadeh A, Ghaffari SH . Blockade of TLR4 using TAK-242 (resatorvid) enhances anti-cancer effects of chemotherapeutic agents: a novel synergistic approach for breast and ovarian cancers . Immunologic Research . 67 . 6 . 505–516 . December 2019 . 32026322 . 10.1007/s12026-019-09113-8 . 211048929 .
• Zandi Z, Kashani B, Bashash D, Poursani EM, Mousavi SA, Chahardoli B, Ghaffari SH . The anticancer effect of the TLR4 inhibition using TAK-242 (resatorvid) either as a single agent or in combination with chemotherapy: A novel therapeutic potential for breast cancer . Journal of Cellular Biochemistry . 121 . 2 . 1623–1634 . February 2020 . 31535397 . 10.1002/jcb.29397 . 202689986 .

Notes and References

1. Wang X, Smith C, Yin H . Targeting Toll-like receptors with small molecule agents . Chemical Society Reviews . 42 . 12 . 4859–4866 . June 2013 . 23503527 . 3665707 . 10.1039/c3cs60039d .
2. Karimy JK, Reeves BC, Kahle KT . Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury . Expert Opinion on Therapeutic Targets . 24 . 6 . 525–533 . June 2020 . 32249624 . 8104018 . 10.1080/14728222.2020.1752182 .
3. Miller S, Blanco MJ . Small molecule therapeutics for neuroinflammation-mediated neurodegenerative disorders . RSC Medicinal Chemistry . 12 . 6 . 871–886 . June 2021 . 34223157 . 8221257 . 10.1039/d1md00036e .
4. Innao V, Rizzo V, Allegra AG, Musolino C, Allegra A . Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma . Cells . 10 . 2 . 439 . February 2021 . 33669515 . 7922387 . 10.3390/cells10020439 . free .
5. Dickinson SE, Wondrak GT . TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis . Current Medicinal Chemistry . 25 . 40 . 5487–5502 . 2018 . 28847267 . 10.2174/0929867324666170828125328 . 670318 .