In our latest company interview we continue our ongoing AACR series on various protein degraders and how they may be useful in hitting difficult targets where small molecule TKIs have struggled mightily for various reasons, which we discuss in detail.
The protein degraders are what we might call large small molecules – they have a large molecular weight in Dalton terms – yet despite their unwieldy size they do offer a number of distinct benefits, which could potentially lead to improved efficacy, reduced toxicity, and enhanced outcomes in the setting of both cancer and autoimmune disease. At least this is nice in theory, but what actually happens in practice?
Can we learn from the preclinical rationale and experiments to get a sense of what might happen in the clinic?
Find out more about what one emerging young biotech are accomplishing on the protein degradation front in both hematologic malignancies and solid tumours…
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In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!
Is it time-up for the bromodomain class?
Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.
Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.
Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.
The same evolution may possibly happen in the BET/bromodomain space too.
The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.
Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?
The short answer is yes… but what are they and who owns them?
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