Capivasertib: the seventh approved fragment-derived drug

On Thursday last week the FDA approved capivasertib for certain breast cancer patients. This marks the seventh fragment-derived drug to be approved. It is also the first approved drug targeting the kinase AKT.

 

Practical Fragments first wrote about capivasertib, then called AZD5363, way back in 2013, where we described the decade-long odyssey from fragment to drug. Interestingly that fragment, 7-azaindole, was also the starting point for two other approved drugs, pexidartinib and vemurafenib. As we noted at the time, “high-affinity molecules were obtained relatively quickly, but these still required a huge amount of effort to achieve selectivity, oral bioavailability, and other properties.”

 

What happened next is a poster child to counter one of the false beliefs Christopher Austin noted as being widespread outside industry: “Once an investigational therapy gets into humans for the first time, regulatory approval and marketing are all but assured.”

 

Capivasertib entered the clinic in 2010 in the first of more than 30 studies listed on ClinicalTrials.gov to date. One challenge was finding patients that would benefit sufficiently to offset a long list of side effects, including diarrhea and glucose fluctuations. In the end, the current approval is in combination with fulvestrant for “adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.”

 

Needless to say, these were not the first patients tested. Use of genetic testing to match patients with a drug likely to help them is not routine even today, let alone in 2010. Managing side effects also required figuring out how much of the drug to dose and how often. But additional combination trials are ongoing. Perhaps, as with venetoclax, capivasertib will eventually prove to be useful for a wider range of patients.

 

The first marketed fragment-derived drug, vemurafenib, sprinted from program initiation to approval in just six years. Capivasertib took twenty. As we previously noted, success in drug discovery is not necessarily fast or inevitable. Every year more than 40,000 people die of breast cancer in the US alone, but the death rate has slowly been declining. Hopefully the introduction of capivasertib will continue to reduce this.

 

Congratulations to all the researchers at AstraZeneca, Astex, and the Institute for Cancer Research for participating and persisting in this 20-year marathon to bring a new treatment to people with cancer.

Fragments in the clinic: AZD5363

As illustrated earlier this year, kinases have been a fertile field for fragments. In a recent issue of J. Med. Chem., Jason Kettle and colleagues at AstraZeneca describe the discovery of AZD5363, a protein kinase B (PKB) inhibitor currently in multiple phase I clinical trials for solid tumors.

The story actually starts a decade ago, with a collaboration between Astex and the Institute of Cancer Research. The two organizations were interested in PKB (also known as Akt1), which has a central role in the PI3K signaling cascade. Virtual, biochemical, and crystallographic screens identified small fragments such as substituted pyrazoles and 7-azaindole (which astute readers will recognize as the starting point for vemurafenib) that bind to the so-called hinge region of PKB. Structure-guided fragment-growing ultimately led to compound 2.

This compound, while potent against PKB, was unselective against the related protein kinase A (PKA), so further crystallographically-enabled medicinal chemistry led to CCT128930, with 30-fold selectivity against PKA. This compound had limited oral bioavailability, so further optimization led to compound 3.

In 2005, Astex partnered this program with AstraZeneca, which is presumably where the current paper picks up. Although compound 3 had good pharmacokinetics and was selective against PKA, it inhibited the kinase ROCK2, which regulates blood pressure; it was also a modest hERG inhibitor. Extensive SAR explorations around the hinge-binding element, the amine, and the aromatic group were not productive, but substitution off the benzylic position was tolerated. Adding a basic substituent dramatically reduced hERG binding, but at the cost of oral bioavailability. However, adding a variety of neutral, polar substituents led ultimately to AZD5363, which has no detectable hERG inhibition, good selectivity against ROCK2, and improved solubility and cell activity.

This paper nicely illustrates some of the challenges in drug discovery: high-affinity molecules were obtained relatively quickly, but these still required a huge amount of effort to achieve selectivity, oral bioavailability, and other properties. Indeed, only three heavy atoms differentiate compound 3 from AZD5363, but it took a heroic effort to get there.

Finally, it is worth noting that this research was done at Alderley Park, which attendees of Fragments 2009 will remember fondly. Sadly, AstraZeneca has announced that they will be closing this site. There are many very talented scientists there, and Practical Fragments wishes all of them the best of luck.

Current Topics in Medicinal Chemistry Special FBDD Issue

This year ends with an entire issue of Current Topics in Medicinal Chemistry devoted to FBDD. Rob van Montfort and Ian Collins provide a brief editorial overview of the six papers. Collins and colleagues also describe their application of fragment-based methods to develop inhibitors of the anti-cancer target protein kinase B (AKT).

Half the papers cover various forms of fragment screening: the Medical Structural Genomics of Pathogenic Protozoa Consortium describes their crystallographic approach, Helena Danielson discusses the use of SPR, and Gregg Siegal and Johan Hollander present their Target Immobilized NMR Screening (TINS) methodology.

Charles Reynolds and colleagues review metrics, such as ligand efficiency and fit quality, for evaluating fragment hits.

Finally, in the longest article in the collection, Vicki Nienaber discusses how fragment-based methods may be particularly useful for discovering compounds that will cross the blood-brain-barrier to target the central nervous system.

As 2009 comes to a close, Practical Fragments would like to thank our readers, old and new. May you all have a happy and productive 2010!