Calithera Biosciences, Inc. announced that it will present the first data from its preclinical synthetic lethality pipeline at the American Association for Cancer Research 2022 Annual Meeting. The accepted poster will detail Calithera's discovery of a novel series of vacuolar protein sorting-associated protein 4A (VPS4A) inhibitors that are currently advancing through lead optimization. VPS4A and VPS4B are paralog ATPases essential for remodelling intracellular organelle membranes.

Membrane remodelling is an essential cellular function and loss of function of both VPS4 paralogs is lethal to cells. The preclinical data demonstrate that VPS4A genetic inhibition in cell lines with loss of VPS4B preferentially showed profound death in cancer cells. Calithera is building a robust preclinical pipeline of additional synthetic lethality targets with a continuing focus on paralog genes.

Gene paralog pairs represent a promising class of synthetic lethal cancer targets. When a tumor cell loses one paralog, the cell is dependent on the second paralog to carry out an essential cellular process, since loss of both paralogs leads to tumor cell death. Calithera researchers have confirmed VPS4A and VPS4B as synthetic lethal paralog pairs, noting that both homozygous and heterozygous loss of VPS4B in cancer cells makes them vulnerable to VPS4A inhibition.

VPS4B is lost in a heterozygous fashion in the majority of colorectal cancer, pancreatic ductal adenocarcinoma, ovarian, esophageal and head & neck cancers and is deleted in large numbers of other tumor types. At AACR 2022, Calithera will report the discovery of a series of novel, small-molecule VPS4A inhibitors which have potential in the treatment of VPS4B-deleted tumors.