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Drug Discovery
Degrader technology: antivirals and cancer.
A recent example is our depsin based PROTACs as shown below. These compounds target the cyclophilin protein in cells to inhibit HIV-1 infection. The combination of the cyclophilin macrocycle and the E3Ligase ligand enable selective degradation of this cyclophilin protein over closely related proteins. The synthesis of these molecules can be seen here: . Other degrader technology is in development
Selective cyclophilin-A degradation and potent HIV-1 activity.
Neuropilin: a link between vascular biology, cancer and pain.
The cell surface protein neuropilin-1 is a receptor for several growth factors. These can control signalling in blood vessels, immune regulation for cancer, and as has been recently shown for pain signalling. We were the first to develop inhibitors of neuropilin-1 as reported here and with more potent analogues here:
The structure and orientation in the neuropilin-1 binding site as shown by X-ray crystallography.
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Exploiting the big conductance potassium ion channel to protect nerves and support CNS signaling.
The big conductance potassium channel (BK channel) has numerous physiological functions but in the CNS its dysfunction can cause neurodegeneration and intellectual disability. We discovered an isoform specific activator drug (VSN16R) of the channel which has been studied in the clinic as both an anti-spastic agent and for its role in neuroprotection. 听听 听 . BK channel polymorphisms are associated with numerous intellectual disability genes, VSN16R can fix many of these deficits in experimental models such as of Fragile X syndrome.
Simplified diagram to show myelin distribution around neurons. Oligodendrocytes (green), grow myelin sheaths around axons projecting from neurons (blue). Astrocytes (brown) are in close proximity.
Select publications
- Hurley, MJ, Deacon听RMJ, Chan听AWE, Baker听D, Selwood听DL听& Cogram听P听(2022). . Brain.听Vol.听145(1):听76-82.
- Radin听DP, Caponegro听M, Smith听G, Moushiaveshi听V, Selwood听D听& Tsirka听S听(2022). . FASEB Journal, Vol. 36(51).
- Scott听OB, Gu听J听& Chan听AWE听(2022). . Journal of Chemical Information and Modeling.听J Chem Inf Model.听Vol.听62(22): 5383-5396.
- Selwood听DL, Mota听F, Yelland听T, Hutton听JA, Parker J, et al. (2021). . ChemBioChem.
- Gregson听A, Thompson听K, Tsirka听SE听& Selwood听DL听(2019). . F1000Res, 8.
- Briggs LC,听Chan AWE, Davis CA ...听Selwood DL, Collins MK, Barrett TE (2017).听. J Virol. Vol. 91(23). pii: e01170-17.
- Baker D, Pryce G, Visintin C, Sisay S, Bondarenko AI听...听Selwood DL听(2017).听. Br J Pharmacol. Vol. 174(16): 2662-2681.
- Prak K, Kriston-Vizi J,听Chan AW, Luft C, Costa JR, Pengo N, Ketteler R.听. Biochemistry. Vol. 55(3): 608-17.
- Warne J, Pryce G, Hill JM, Shi X ...听Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL (2016).听. J Biol Chem. Vol. 291(9): 4356-73.
- Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC,听Selwood D, Tsirka SE (2016).听. Oncotarget. Vol. 7(9): 9801-14.
- Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C,听Chan AW, Riddall D, Garthwaite J, Baker D,听Selwood DL听(2014).听. J Med Chem. Vol.听57(7): 2942-52. Erratum in: J Med Chem. Vol. 58(8): 3637.
Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C,听Chan AWE ...听Selwood DL, Baker D听(2014).听. Brain.听137(Pt 1): 92-108.
Moyes AJ, Khambata RS, Villar I, Bubb KJ ...听Selwood DL, Ahluwalia A, Hobbs AJ (2014).听. J Clin Invest. Vol. 124(9): 4039-51.
Aldeghi M, Malhotra S,听Selwood DL,听Chan AW听(2014).听. Chem Biol Drug Des. Vol. 83(4): 450-61.
Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA,听Selwood DL et al.听(2013).听. Nature. Vol. 503(7476): 402-405.
Chan AW, Laskowski RA,听Selwood DL听(2010).听. J Med Chem. Vol. 53(8): 3086-94.
Okuyama M, Laman H, Kingsbury SR, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL (2007).听. Nat Methods. Vol. 4(2):153-9.
Funding and Partnerships
