Category Archives: medicinal chemistry

Tackling challenging targets with Chemotype Evolution

Carmot Therapeutics, a small company located in San Francisco’s Mission Bay, has developed a very innovative drug discovery technology, called Chemotype Evolution (CE), that relies on fragment-based discovery but is different from traditional FBDD and HTS approaches in important ways.

The first important innovation is that CE relies on a “bait” molecule as a starting point for screening.  The bait can be a known ligand, cofactor, or inhibitor.  The bait is then derivatized with a linker moiety that allows it to become chemically bonded with every fragment in a proprietary library.  This process generates a screening library that contains thousands of bait-fragment hybrids.  These hybrids are then screened against the target for binding using either biophysical or biochemical screening techniques in a high-throughput plate format.

The most powerful aspect of CE is the ability to iterate over chemical space, allowing access to an exponential number of possible fragment-bait hybrids.  The method can be iterated with new “baits” derived from the best fragment hits of the previous round.  Thus, instead of having 7,000 fragments in your library, after 3 iterations you access 7,000^3 possible combinations (343 billion possible compounds), selecting only the most target-relevant chemotypes at each stage. 

figure-image

Schematic of the Chemotype Evolution process through 3 iterations. Note that at any point after each iteration, the hit molecules can be taken into hit-to-lead optimization.

The CE approach is similar in concept to the “tethering” approach pioneered at Sunesis, but differs in the fact that no protein engineering of cysteine residues needs to be performed.  The bait molecule performs the role of the engineered cys, providing a “handle” that binds to the target and selects for complementary fragment binders.

Carmot Therapeutics just embarked upon their first major industry collaboration with the January 2014 announcement of a partnership with Amgen to use CE technology against two challenging targets.  Identifying leads and developing hits will be carried out jointly between the companies, while clinical trials will proceed at Amgen.  I think Carmot is definitely a company to watch given its innovative and potentially paradigm-shifting discovery technology and increasing interest from big pharma. 

 

 

 

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Rethinking drug action: activating an ion channel to treat Cystic Fibrosis

In my first “Rethinking Drug Action” post, I described how researchers are seeking activators of PARK9, a protein that is mutated in Parkinson’s Disease.  In a similar manner, Ivacaftor, a new drug for Cystic Fibrosis (CF), shifts the paradigm from treating CF symptoms to therapeutic treatment of the underlying cause of the disease: defects in the activity of the CFTR ion channel owing to genetic loss-of-function mutation.

The molecular structure of Ivacaftor (Kalydeco).

The molecular structure of Ivacaftor (Kalydeco).

In this case the mutation is the rare G551D variant (4-5% of all CF patients) that makes CFTR non-responsive to ATP-dependent channel opening.  The more common delta-F508 CFTR mutation is thought to prevent membrane expression of CFTR through misfolding, and indeed, clinical trials showed that ivacaftor alone had no effect on patients with this mutation.

However, for patients with the G551D mutant, where CFTR does reach the membrane but is less active than WT, the drug is very efficacious.  In a clinical trial, patients who received ivacaftor were 55% less likely to experience pulmonary exacerbation (defined as a worsening of lung function owing to infection or inflammation) after 48 weeks on the drug.  Other markers of CF were also improved during this period.

The exact mechanism of action of ivacaftor is not known. Interestingly, however, ivacaftor enhances spontaneous ATP-independent activity of both G551D-CFTR and WT-CFTR to a similar magnitude.  In a recent PNAS paper, researchers propose that ivacaftor affects both WT and G551D in the same way, namely by shifting the equilibrium from the closed (C2) state towards the open2 (O2) state, in essence, “wedging” CFTR open.

Proposed mechanism of CFTR gating from the PNAS paper cited below.  Ivacaftor is thought to stabilize the O2 form over the C2 form.

Proposed mechanism of CFTR gating from the PNAS paper cited above. Ivacaftor is thought to stabilize the O2 form over the C2 form.

In the same paper, the researchers propose that the CFTR transmembrane domains (TMD) may be the site of binding for the drug.  In support of this, they note that the drug is relatively hydrophobic and is measured to increase gate opening times regardless of whether it is applied from the cytoplasmic or extracellular side, suggestion membrane permeation and binding to the TMDs.

More studies are needed to prove this mechanism, but it will be very interesting to see how this paradigm-shifting new drug works on the molecular level.  In addition, other compounds are in development that aim to enhance the folding and membrane expression of the more common DF508 mutation.  Perhaps combination therapy with new compounds for DF508 and ivacaftor together will aid those CF patients who currently are not helped by ivacaftor alone.

Why are many drugs aromatic heterocycles?

To the non-specialist in medicinal chemistry (like myself), the abundance of drugs that contain aromatic ring moieties, usually with heteroatoms like N, is somewhat surprising. In fact, in 2012, the top 4 out of 5 drugs by sales contain such groups. 

There are at least a few good reasons why these types of compounds appear so often:

1 Heterocyclic systems are easier to prepare synthetically than all-carbon based aromatic systems and they are easier to modify later.

2  Scaffolds with heterocycles allow the easy introduction of H-bond donors and acceptors to fine-tune the properties of the compound, like binding affinity, solubility, and resistance to metabolism in vivo.

3 Can “template hop” easily off of aromatic ring scaffolds to evolve new IP with the same functionality as a known drug (e.g., Viagra to Levitra).

Can synthetic chemistry specialists give more reasons?  (Post in the comments!) 

Source:  Jordan, A, Roughley, S.  “Drug discovery chemistry: a primer for the non-specialist.”  Drug Disc Today, 14. 2009