3rd generation EGFR TKIs

Here is a topical paper (Robert Heald et al; J. Med. Chem. 2015, 58, 8877-8895) by the group at Argenta/Genentech on the discovery of third generation EGFR tyrosine kinase inhibitors. First generation EGFR TKIs like Gefitinib or Erlotinib show convincing early responses in lung cancer, but resistance quickly develops that has limited their overall effectiveness. A recent study published in the British Journal of Cancer (2014, 110, 55-62) that looked at 106 patients with EGFR sensitising mutations showed a 70% response rate to Gefitinib and progression free survival of 9.7 months. Approximately 60% of the acquired resistance is caused by a T790M mutation of the gatekeeper residue that substantially reduces the affinity of first generation inhibitors for the ATP binding site. Several pharma companies are in competition to market a new generation of EGFR TKI’s that also inhibit the mutated kinase. Recent news from the FDA announced the approval of AstraZeneca’s TagrissoTM ahead of the Clovis drug, Rociletinib, for treating patients with EGFR T790M mutation positive metastatic non-small cell lung cancer. Together with the recently approved companion diagnostic, CobasTM, TagrissoTM could see rapid uptake in the clinic with estimated sales potential of $3 billion. (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472525.htm)

The T790M mutation reduces the effectiveness of first generation inhibitors by both occluding a portion of the ATP binding site and increasing the enzymes’ affinity for ATP. To overcome the low Km[ATP], both Clovis and AstraZeneca have targeted the mutant tyrosine kinase with covalent modifiers that juxtapose the poorly conserved Cys797 with an acrylamide acting as a Michael acceptor. Unlike the second generation inhibitors, both compounds show good selectivity against the wild-type EGFR. Unfortunately, the EGFR is a moving target with the potential for further mutations always one step away.

The lead optimisation case study published by the Argenta/Genentech group comments on recent reports of a C797S mutation in samples from patients who have developed resistance to third generation therapies. Loss of the cysteine nucleophile would render the third generation covalent inhibitors ineffective, but how quickly this becomes a problem will have to await further clinical study.

To address this concern the Argenta/Genentech medicinal chemists have designed a non-covalent inhibitor. Among the challenges are the low Km[ATP] of the mutant EGFR kinase requiring inhibitors to have high affinity for the ATP binding site to overcome the large intracellular ATP concentrations. The paper builds on their initial publication (J. Med. Chem. 2014, 57, 10176-10191) that identified potent and selective inhibitors based on a 4-imidazopyridine substituted diaminopyrimidine scaffold. Their second paper focuses primarily on the DMPK challenges towards designing compounds with predicted low to moderate in vivo human clearance. However, in doing so it covers many areas of medicinal chemistry with an amalgamation of DMPK, structure based design and lead optimisation metrics. In the authors words; “ …this work highlights a number of aspects of medicinal chemistry doctrine: the structural similarity of leads and optimised compounds, the utility of fluorine in the optimisation of small molecule drugs, and the judicious application of compound quality metrics as an aid to interpretation of SAR”. I would also add to the list, in vivo mouse xenograft PK/PD that clearly shows biomarker modulation consistent with the free drug hypothesis, and some ambitious chemistry with the final compound containing no fewer than 4 chiral centres!

Darren 16-12-2015 Picture 1

Darren 16-12-2015 Picture 2

Compound 42 was administered orally (po) to H1975 tumor-bearing mice once a day for 3 days with either 100 or 300 mg/ kg, respectively. Tumors were collected at indicated times (after last dose), and phosphorylation of EGFR, ERK, and AKT was determined using commercially available MSD assays. Lines on the free concentration plot show the in vitro H1975 p-EGFR IC50 and IC90. Error bars represent the mean ± SD. Plasma concentrations of 42 were measured using a liquid chromatography−tandem mass spectrometry assay, and free concentration was calculated using Fu of 0.207.

The authors suggest follow up studies on highlighted compounds to demonstrate an improved therapeutic index over current third generation treatments and evaluating the potency against C797S mutant cell lines.

I can’t find any mention of them on the current Genentech pipeline. Does anybody know about their progress?

Blog written by Darren Le Grand


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