Case Nos: CA-2024-002655/002675/002676 - [2025] EWCA Civ 936

The Slides

The Slides are slides from a presentation given by Charles Sawyers at the Retreat. The judge described what the Slides would disclose to the skilled team at [346]-[365], much of which is reproduced below.

The skilled team would understand from the Slides that the authors were investigating compounds for use in the treatment of HRPC. They would further understand from the Slides that it was important for such compounds to be AR antagonists and not to act as agonists.

Slides 5-7 describe the general approach of the authors in seeking compounds that were stronger antagonists of AR than bicalutamide, but without showing agonist activity in cells that overexpressed AR.

Slide 8 is a summary of “Design, Synthesis and SAR studies” that the authors have carried out. This is agreed to be a key slide. It explains that certain design tools were used to initially arrive at the compound shown as RU59063. This has high AR binding affinity but agonistic activity. Prof Westwell described the structure of RU59063 by reference to the circled parts shown in the figure below.

The yellow ring shows a 6-membered aromatic ring (phenyl) with two substituents: a cyano (CN); and a trifluoromethyl (CF₃) group. The medicinal chemist would note that the same disubstituted phenyl ring is present in bicalutamide. The blue ring shows a heterocyclic five-membered ring with sulphur and oxygen substituents, known as a thiohydantoin. The green ring shows a hydroxybutyl (C₄H₈OH) group bound to one of the nitrogen atoms of the thiohydantoin ring. The red ring shows two methyl groups (a geminal dimethyl group) at the bottom of the structure bound to a carbon atom of the thiohydantoin ring.

Slide 8 also shows a pharmacophore (reproduced below). A pharmacophore provides an overview of the authors’ views of different interactions of a molecule within a binding site (in this case, the interactions of the molecules under study within the AR binding site). The targets for investigation are marked R, R₁ and R₂.

The medicinal chemist would note the following about this figure:

The left-hand side (LHS) of the pharmacophore indicates that the cyano group (NC) at the 4 position of the LHS phenyl ring is important for hydrogen bond interaction and that the trifluoromethyl group (F₃C) at the 3 position of the LHS phenyl ring is important for hydrophobic interaction. The LHS of the pharmacophore is structurally the same as the LHS substituted phenyl rings of both RU59063 and bicalutamide.

The LHS phenyl ring (shaded yellow) and part of the middle thiohydantoin ring (shaded turquoise) are indicated as being important for binding affinity to the AR. This part of the thiohydantoin ring is structurally the same as the thiohydantoin ring of RU59063. Bicalutamide does not have a thiohydantoin ring.

The left-hand side of the structure (in yellow and blue) are indicated as important to binding affinity to the AR and shown as fixed (i.e. no change).

The remaining part of the middle thiohydantoin ring (shaded red) is indicated as being important for hydrophobic interactions with the AR. The geminal dimethyl group (red) is generalised from RU59063 by the use of two further placeholder groups, shown by R₁ and R₂.

The right-hand side (RHS) (shaded green) is another phenyl ring and is said to provide “antagonist activity”, with the phenyl ring also providing “rigidity”. The medicinal chemist would understand that rigidity is obtained because a phenyl ring is a flat and rigid group that can only rotate on its axis. This contrasts to RU59063 (which is said to have agonistic activity) which did not have rigidity in this position, as its flexible alkyl chain can take on lots of different configurations. The experts agreed that the medicinal chemist would therefore understand that the key development in this structure over RU59063 is the introduction of the “right” (green) phenyl group, with this moiety seemingly resulting in the molecule having the desired antagonistic activity without agonistic activity.

Slide 9 shows the structure of RD37 and describes it as a potent antagonist in hormone sensitive LNCaP cells. Data is presented that shows RD37 reducing relative PSA levels in a dose-dependent manner compared to bicalutamide and RU59063. RD37 exemplifies the pharmacophore of slide 8 in that:

In place of R₁ and R₂ at the C5 position of the middle thiohydantoin ring is a cyclobutyl (a four-membered carbon ring).

In place of R at the 4 position of the RHS phenyl ring is a methyl group (CH₃).

Slides 10-15 present further data relating to RD37, setting out its benefits, including that it acts as an AR antagonist in HRPC cell lines without agonist activity (slides 10, 11), that it shows selectivity for AR (slide 12), that it has comparable binding affinity to bicalutamide (slide 13), and that it slows the growth of HRPC cell line in vivo compared to bicalutamide. Slide 15 provides some PK and PD data on RD37, showing that it has a short serum half-life and is cleared after around 6 hours.

Slide 16 presents the structures of two derivatives of RD37: RD131 and RD162. It also presents PK data relating to these compounds and also bicalutamide. This is materially the same as the data that is shown in the Poster (see paragraph 39 above), the only difference is that the text below the chart on slide 16 makes it clear that the serum concentrations were measured after IV dosing, whereas this is not stated in the Poster. This slide shows that RD37 has PK problems, with high logP values (too lipophilic) and its PK after dosing is poor (almost all gone after 15 hours). No steady state value can be given.

The box on slide 16 indicates that the inventors had then tried a number of different compounds (the structures of RD131 and RD162 being shown) with RD162 having good IC₅₀ values, reasonable LogP and good steady state concentration, when compared to bicalutamide. Of the three molecules disclosed on this slide, RD162 performs by far the best in PK after IV dosing, where it shows promising performance as compared to bicalutamide.

Slide 17 shows how RD37, RD131 and RD162 perform in a cell-based assay mimicking HRPC, measuring relative PSA levels. RD37, RD131 and RD162 all show an antagonist-type dose response with increasing concentrations.

Slide 18 states the following conclusions:

“Cell-based screens can be used to identify anti-androgens with greater potency than bicalumatide [sic] while avoiding the undesirable agonism side-effect

SAR has defined a thiohydantoin imine derivative of the high affinity ligand RU59063 as an attractive lead

Greater potency can be achieved in the absence of greater binding affinity, presumably through inducing altered AR conformation

Further in vivo studies are in progress to define an optimal clinical candidate”

The experts were agreed that the first three conclusions summarise the key points from the preceding slides (even though the reference to “imine” would not be understood).

The experts were also agreed that the “Further in vivo studies” were in progress to optimise the PK properties of RD162, since there is no doubt that the most promising candidate identified in the Slides is RD162. In other words, the lead compound from the Slides (taking into account both activity and PK data) is RD162. 

RD162 shares the structure of RD37 with different substitutions being made to the right-hand phenyl ring (a methylamide group directly attached to the ring with an added fluorine on that phenyl ring). As with the other compound depicted in the Slides (namely, RD131), RD162 retains the cyclobutyl on the central ring, a feature of RD37.