A novel small-molecule drug platform to silence cancer targets –. Application to
the pan-ErbB kinases. Russell C. Petter, Erica Evans, Margit Hagel, Russell Karp
...
A novel small-molecule drug platform to silence cancer targets – Application to the pan-ErbB kinases
AACR 2009 Denver, CO Abstr. 3746
OPTIONAL LOGO HERE
Russell C. Petter, Erica Evans, Margit Hagel, Russell Karp, Mariana Nacht, Michael Sheets, Thia St. Martin, William Westlin, and Juswinder Singh Avila Therapeutics Inc. 100 Beaver Street, Waltham, MA 02453
Superior Biochemical Activity Against EGFR Mutants
We have developed a novel drug design platform that enables the rapid identification of small-molecule inhibitors that covalently modify their targets, leading to specific and durable silencing of the targeted protein. These inhibitors will have higher potency, improved specificity, and longer duration of action, leading to less frequent dosing and lower toxicity. Importantly covalent drugs afford a unique translational advantage in that monitoring target occupancy is straightforward and this in turn will inform appropriate dosing. We have successfully applied our platform to multiple drug targets (eg. c-Kit, PDGFR, Btk) and here we illustrate our approach using the pan-ErbB family of tyrosine kinases. The ErbB family of receptors is over-expressed in a wide variety of tumors and the therapeutic benefits of inhibiting EGFR and ErbB2 have been clinically validated. Blocking both of these receptors with an orally active small-molecule inhibitor provides a potential treatment for many cancers including NSCLC, breast and colorectal cancers. Using our drug design platform, we have identified a novel chemical class that potently and covalently inhibits EGFR and ErbB2. Our compounds effectively silence wildtype EGFR, EGFRs with clinically observed activating mutations, drug-resistant mutants of EGFR, and ErbB2. Notably, covalent silencing leads to prolonged cellular duration of action; in A431 cells, EGFR is effectively inhibited for at least 18 hours after compound removal. In xenograft models, using oral dosing, our compounds demonstrate reduction in the growth of A431 ErbB-dependent tumors. Importantly, in a broad kinase panel screen, this class of inhibitors shows exquisite selectivity compared to clinical ErbB inhibitors such as erlotinib and neratinib. Moreover, using a biotinylated analog of our covalent inhibitors, we can directly quantify target occupancy in a dose- and time-dependent manner. This will guide our in vivo treatment schedules and will directly translate into better informed clinical dosing to maximize efficacy while minimizing offtarget toxicities. Overall, this novel class of ErbB protein silencing drugs offers an exciting new therapeutic option for the treatment of many prevalent and aggressive cancers.
Table 1. CNX-222 and CNX-174 are potent inhibitors of wt-EGFR and are more potent than erlotinib or lapatinib against clinically important EGFR mutants. IC50 determined by monitoring phosphorylation of Omnia peptide Y12-SOX over one hour following a 30-min preincubation. [ATP] = KMapp.
Compound ID
EGFRWT
EGFR T790M
EGFR T790ML858R
CNX‐174
8 hours.
AVL Inhibited target
Free target
Avila’s approach affords potentially best-in-class pan-ErbB inhibitors
*
Inhibited target
Covalent Probe carrying detection label
9 Avila compounds suppress tumor growth in human tumor xenograft models.
These findings point to the broader value of protein silencing: 9 Long-acting but with less overall exposure (PD > PK) 9 Novel and improved selectivity profile with potential for better safety
AVL
*
AVL Inhibited target
9 Retained efficacy over mutational resistance 9 Modified target protein is a built-in biomarker of drug activity
