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Introduction
Exscientia, a leading AI-driven drug discovery company, has recently announced the expansion of its precision oncology pipeline. The company has successfully developed two promising candidates, EXS74539 ('539) and EXS73565 ('565), which target specific molecular pathways involved in cancer. These precision-designed molecules have the potential to provide significant benefits to patients and overcome design limitations seen in traditional drug discovery approaches.
Precision Design for Improved Success
Exscientia's precision design platform utilizes artificial intelligence (AI) to optimize the development of novel therapeutics. By leveraging AI algorithms, the company can efficiently solve complex design issues that may hinder the success of other compounds. This approach increases the probability of success for their precision oncology candidates.
Collaboration with Celgene and Bristol Myers Squibb
The development of both '539 and '565 was made possible through a collaboration between Exscientia and Celgene, which was later acquired by Bristol Myers Squibb (BMS). Under the collaboration, the molecules met the criteria for BMS to exercise its option. However, BMS's options have now lapsed, and Exscientia maintains all worldwide rights to both compounds.
Promising Characteristics of EXS74539 ('539)
EXS74539 ('539) is a differentiated lysine demethylase 1 (LSD1) inhibitor with potential applications in both haematology and oncology. LSD1 plays a critical role in regulating the expression of genes associated with tumor growth and survival. Previous LSD1 inhibitors in development have faced challenges in achieving suitable pharmacokinetics, brain penetrance, and reversible mechanism of action. However, Exscientia's precision-designed candidate, '539, demonstrates appropriate CNS penetration, making it effective against brain metastases, which are prevalent in certain cancer subtypes. In preclinical studies, '539 showed favorable activity in small cell lung cancer (SCLC) xenograft models, inhibiting tumor growth in a dose-dependent manner. The molecule also exhibits a favorable absorption, distribution, metabolism, and excretion (ADME) profile, with a predicted human half-life that addresses previous limitations in LSD1 inhibitors.
Key Attributes of EXS73565 ('565)
EXS73565 ('565) is a mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease inhibitor with potential applications in haematology. MALT1 is a protease crucial for the activation of the NF-κB pathway, which supports the uncontrolled proliferation of malignant T- and B-cells in haematological cancers. Exscientia's precision design approach optimizes the safety profile of '565 while maintaining potency and selectivity. Other MALT1 inhibitors in clinical development have shown significant inhibition of UGT1A1, an enzyme involved in bilirubin metabolism, leading to dose-limiting toxicities. However, '565 demonstrates minimal inhibition of UGT1A1, allowing for an acceptable therapeutic index. In vivo studies have shown anti-tumor activity in mouse models, both as a monotherapy and in combination with ibrutinib, a commonly used targeted therapy.
Future Clinical Development Plans
Exscientia plans to provide an update on its clinical development plans for these precision oncology candidates during the second half of this year (2023). The company is currently conducting investigational new drug (IND) enabling studies to support the progression of these molecules into clinical trials. With the success of their CDK7, A2A, and PKC-theta programs, Exscientia is confident that their AI-driven precision design platform will continue to deliver innovative drug candidates. The company aims to achieve four clinical stage compounds by 2024, further solidifying their position as a leader in AI-driven drug discovery.
Conclusion
Exscientia's expansion of its precision oncology pipeline with the development of EXS74539 ('539) and EXS73565 ('565) demonstrates the power of AI-driven drug discovery. These precision-designed candidates address challenging target profiles and offer potential benefits to patients with haematologic and solid tumors. By leveraging AI algorithms, Exscientia has overcome limitations seen in traditional drug discovery approaches, providing a more efficient and effective way to develop novel therapeutics. With ongoing collaborations and a robust pipeline, Exscientia is poised to revolutionize the field of drug design, discovery, and development, ultimately improving patient outcomes in oncology and beyond.
References
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