Between the 23rd and 27th of August, Amanda Walzer and I represented Cresset at the ACS Fall 2026 conference in Chicago. Events like this not only give us the opportunity to showcase the tools and capabilities available at Cresset but also give us the chance to learn from the variety of projects being reported by others in the chemistry community. I gave a presentation describing the strategy employed by our Discovery team when tackling a variety of drug discovery challenges.
Topics discussed covered a wide array of themes; from overcoming synthetic challenges to gain access to the correct molecules to progress the project, small molecules drug discovery along with beyond rule of five compounds such as antibody drug conjugates (ADCs), therapeutic peptides, and degraders, along with data-driven, computational, and platform enabled drug discovery. In addition to these broad categories, there were also several focused sessions. Of particular interest to me, especially considering the topics covered in my presentation, was the session celebrating the impact of oncologic and antiviral drugs on human health (Figure 1A).
Figure 1. (A) Oncology drug – Lorlatinib, bound to TKI (5A9U). (B) MRTX1133 bound to WT-KRAS (9O0N).
The importance of KRAS, and its mutants, was singled out as a target of significant value. With speakers discussing strategies that can be applied to either selectively target individual KRAS mutants or multiple KRAS mutants (Figure 1B). This session wasn’t limited to only small molecule inhibitors; a targeted degradation approach was also described as an alternative strategy.
One of the main attractions at the conference was the first disclosures of clinical candidates, where 13 new compounds were described, for treatment of a variety of diseases such as various cancers, autoimmune diseases, dermatology, anti-inflammatory disease, anti-infective disease, and obesity. Hong Lin from Quanta Therapeutics continued the KRAS focus, introducing their KRAS G12D inhibitor – QTX3034, as a potential treatment for endometrial cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.
Finally, I would like to highlight Ramsay Beveridge’s presentation from Ventus Therapeutics. In this thought provoking talk the application of a relatively unusual pyrone system was discussed, with Beverage’s aspiration being that this success would inspire others the utilise pyrones in their drug discovery campaigns. Iptocigistat (VENT-03) is a cyclic CMP-AMP synthase (cGAS) inhibitor (Figure 2A) developed for the treatment of systemic lupus erythematosus.
Figure 2. (A) 3D structure of Iptocigistat with field points added. (B) Replacement of pyrone with pyridine. (C) Replacement of pyrone with aryl acid. (C) Replacement of pyrone with [1,2,4]triazole[4,3-a]pyridine. (D) Replacement of pyrone with pyraxolo[3,4-b]pyridine. (E) Replacement of pyrone with 2-(1,2,3-triazol-2-yl)pyridine.
Beverage’s encouraged others to apply pyrones in further medicinal chemistry projects asks the question, which systems are pyrones good bioisosteres for? To answer this question, field point analysis of the pyrone system shows that the heterocycle is dominated by the strong electronegative field point between the carbonyl and the methoxy ether group. Therefore, if you are wanting to explore the addition of a pyrone like the one in Iptocigistat, your existing molecule should require this field point too.
Reverse engineering of this pyrone allowed groups that contain this dominate field point to be identified. Not surprisingly, a pyridine ring (Figure 1B) also contained an equivalent electronegative field point, although it is not as prominent as was seen with the pyrone. Interestingly, the identification of an aryl acid (Figure 1C) suggests that a pyrone could be used to replace an acid group to improve bioavailability within a series.
Alternative bicyclic heterocycles that could potentially be replaced with a pyrone include, but are not limited to, [1,2,4]triazole[4,3-a]pyridine (Figure 2D), pyraxolo[3,4-b]pyridine (Figure 2E), and 2-(1,2,3-triazol-2-yl)pyridine (Figure 2F). This strategy of identifying suitable bioisosteres not only allows medicinal chemists to tackle fundamental development issues but also allow the organisation to protect their intellectual property.
The ACS Fall 2026 conference brings together a variety of chemists from multiple disciplines, allowing scientists to present their cutting-edge research that is pushing the boundaries of drug discovery. While it is impossible to cover all the great science that was presented in Chicago, this snapshot gives you a taste for the current advancements being made in the community.
