BMS in-licensed PKC theta inhibitor enters clinical trials

EXS4318 (‘4318), a potentially first-in-class, potent and selective PKC theta inhibitor has entered first-in-human Phase I trials in the US. The compound is in development for immunology and inflammation indications.

PKC theta plays a critical role in controlling T cell function and is a key driver of several highly prevalent autoimmune diseases.

David Hallett, PhD, Chief Scientific Officer at Exscientia explained: “PKC theta is an attractive immune modulating drug target; however, it has been challenging for the field to design a small molecule with the required potency as well as selectivity against other closely related kinases.”

The need for sustained, high levels of target inhibition was required to drive efficacy. In addition, a low daily dose in humans was necessary, so this added to the challenge, according to Exscientia. As PKC theta is structurally similar to several related kinases, it makes it difficult to achieve the high levels of selectivity required to avoid off-target effects.

Promisingly, EXS4318 was identified within 11 months after initiating design of the platform. Hallett added that Exscientia’s “AI design platform was able to deliver a balanced candidate which has demonstrated high on-target activity while maintaining high selectivity and favourable therapeutic index in  Investigational New Drug Application (IND)-enabling studies.”

Bristol Myers Squibb will oversee the clinical and commercial development and Exscientia, who designed the PKC theta inhibitor, is eligible for milestone payments and, if approved, tiered royalties on net product sales.

In May 2021, Bristol Myers Squibb and Exscientia expanded the collaboration in immunology & inflammation indications and oncology.