AZ’8037 / AstraZeneca - LARVOL DELTA

Driving discovery of covalent inhibitors by measuring in cellulo kinetics of on-target engagement (EACR 2023) - "In cellulo kinetics measurement estimated a value of 248 ± 73 M–1 s–1 for kmod/Kiapp, which may be limited by factors affecting actual concentration of inhibitor available in cells for TE. Finally, the cellular TE potencies for compound 25 and analogues estimated using this method correlated well with potency estimates from a target-distal cellular imaging assay.ConclusionThe sensitive UPLC-QQQ MRM MS workflow established allows evaluation of biochemical and cellular target engagement kinetics of covalent inhibitors at a high-throughput scale, opening avenues for application in early drug discovery."

Oncology • Sarcoma • Solid Tumor • KRAS

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer. (PubMed, Mol Cancer Ther) - "Small molecule KRASG12C inhibitors AZ'1569 and AZ'8037 were employed...ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ'1569...Importantly, KRAS amplification and AZ'1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Taken together, combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BCL2L1 • BCL2L11 • EGFR • KRAS • MET

Accelerating the Validation of Endogenous On-Target Engagement and In Cellulo Kinetic Assessment for Covalent Inhibitors of KRAS in Early Drug Discovery. (PubMed, ACS Chem Biol) - "To demonstrate the applicability of the method, KRAS was used as a model system to investigate the interaction of an irreversible covalent small molecule, compound 25, both in vitro and in cellulo...The workflow enabled evaluation of in vitro and in cellulo target engagement kinetics, providing mechanistic insights into the irreversible mode of inhibition. In summary, the method has the potential for target agnostic application in the assessment of on-target engagement of covalent probes compatible with the high-throughput requirements of early drug discovery."

Journal • KRAS

Bcl-xL and association with apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer. (ASCO 2022) - "ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRASG12C MT CRC cells... Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRASG12C inhibitors as a second or third line option."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BCL2L1 • BCL2L11 • EGFR • KRAS • MET