RE: Another blockbuster area for Avacta's Affimers?6 Jun 2020 16:12
OlderWiser-
Some references before understanding:
1.An in vivo inflammatory loop potentiates KRAS blockade BioRxiv
Kristina A.M. Arendt, Giannoula Ntaliarda, Vasileios Armenis, Danai Kati, April 19 2020
2, RAS-inhibiting biologics identify and probe druggable pockets including an SII-a3 allosteric site.
BioRxiv 5th June 2020 Katarzyna Z Haza, View ORCID ProfileHeather et al (article which you may have read on Twitter)
We have identified two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signalling pathways with distinct isoform and mutant profiles. Affimer K6 is the first biologic to bind in the SI/SII pocket, whilst Affimer K3 is the first non-covalent inhibitor of the SII region, revealing a novel RAS conformer with a large, druggable SII/a3 pocket. This work demonstrates the potential of using biologics with small interface surfaces to select novel druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins. KRAS GTPase activity and downstream signaling additionally prerequisites its integration into the cell membrane, which is facilitated by post-translational lipidation and membrane transport of KRAS by various enzymes such as farnesyltransferase (FT), geranylgeranytransferase (GGT), isoprenylcysteine carboxylmethyltransferase (ICMT), phosphodiesterased), and others (Stephen et al., 2014;Simanshu et al., 2017). To this end, therapeutic attempts to inhibit KRAS lipidation by targeting FT/GGT/ICMT were recently coupled by the development of PDEd blockers and of allosteric and covalent inhibitors of mutated KRASG12C (Winter-Vann et al., 2005; Zimmermann et al., 2013; Ostrem et al., 2013).
To make the EXPLANATION simple to understand IMO:
RAS mutations are common oncogenic (Cancer) drivers.These RAS mutations have been found in Pancreatic, Colonic and lung cancers . KRAS proto oncogene is holygrail of anticancer therapy .
It is importanat to note that until now, despite coordinated efforts anti-KRAS DRUG discovery is lagging behind other oncogene targets .
Now that K3 and K6 RAS binding affirmer proteins binding to druggable pockets have been identified to inhibit nucleotide exchange and thus down-stream mutations and cancer pathways . (This also involves complex enzymatic pathways FT, GGT and ITMT as mentioned in para1). Essentially Affirmers potentially offer what some anti-cancer drugs have been unable to do, but will need further studies on this application. IMO
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