Fragments in the clinic: TAK-020

The fifth fragment-based drug approved, sotorasib, acts by irreversibly binding to its protein target. However, despite increasing interest in covalent inhibitors, they are still rare among fragment-derived clinical candidates. A paper just published in J. Med. Chem. by Mark Sabat and colleagues from Takeda describes a new addition.

 

The researchers were interested in inhibitors of BTK, a kinase implicated in cancer as well as arthritis. Indeed, the drug ibrutinib, a covalent BTK inhibitor, has been widely credited with driving recent interest in covalent molecules. Back in 2015 we highlighted work from Takeda describing a fragment screen and optimization to a low nanomolar non-covalent lead. In addition to that fragment, the screen produced triazolone-containing compounds 5 and 6. Crystallography revealed that the triazolone moiety interacts with the kinase hinge region through multiple hydrogen bonds. Importantly, triazolones had not previously been observed as hinge binders. Thus the researchers decided to pursue the chemical space opened up by this discovery.

 

Although compound 6 had higher lipophilicity and lower ligand efficiency than compound 5, it provided better vectors for growing into the binding pocket. Changing the phenyl ring of compound 6 to a pyridyl gave a very slight boost in potency; growing led to low micromolar compound 11. Expanding the pyridyl to an isoquinoline further improved the potency to mid-nanomolar compound 18, which is still fragment-sized and highly ligand efficient. Crystallography suggested how to append an acrylamide warhead to engage cysteine 481 (the target of ibrutinib). This produced TAK-020, which overlays nicely onto compound 6. 

 

The whole campaign was remarkably fast: just 6 months of synthetic effort from fragment to TAK-020.

 

In general, the longer an irreversible inhibitor is incubated with a protein, the more potent it will appear, so IC₅₀ values can vary depending on the assay. A more meaningful number is k_inact/K_i, which turned out to be 205,000,000 M^-1s^-1 for TAK-020, more than 10-fold higher than ibrutinib. The compound demonstrated efficacy in a rat model of collagen-induced arthritis and behaved well in various safety assessments including two-week rat and dog toxicology studies.

 

Based on these results, the compound entered the clinic; the results of a phase 1 trial are reported by Eric Fedyk and colleagues in Clin. Transl. Sci. The compound proved safe and well-tolerated. Although TAK-020 has a relatively short half-life, it led to sustained reduction of BTK activity. (Since irreversible inhibitors by definition remain bound to their targets, their efficacy can be high even if rapidly cleared from the bloodstream)

 

And there the story ends. ClinicalTrials.gov reports that the two phase 1 clinical trials ended more than four years ago, and TAK-020 does not appear on Takeda’s pipeline. Four BTK inhibitors are already approved, with multiple others at various stages of clinical development, so perhaps the molecule was deprioritized for competitive reasons. The fact that TAK-020 first entered the clinic in March of 2015 is a reminder that what you read in the literature often reflects work completed many years ago. Nonetheless, this is a lovely fragment-to-lead story that is well worth perusing.