EVX020, First-in-class KIF20A inhibitor - Next generation ADC payload
Highly selective and potent KIF20A inhibitor
Mechanism of Action identified: both tumor selective and anti-mitotic
Preclinical efficacy demonstrated against multiple hematologic and solid tumors
The KIF20A kinesin
The microtubule associated motor protein KIF20A plays a key role in spindle organization during cytokinesis, the last step of cell division, when the two daughter cells become physically separated [1],[2].
KIF20A is also involved in the function of the Golgi apparatus[3] (the cell’s “traffic center”) where it is responsible for the fission and exit of secretion vesicles [4][5], a mechanism that is essential to ensure the transport of newly synthesized molecules to the cell surface to promote the growth and migration of cancer cells.
KIF20A is overexpressed in many cancers[6][7][8][9][10][11] and this dysregulation is associated with disease progression and poor survival outcome[12][13]. Thus, unlike chemotherapies, KIF20A inhibition should specifically affect cancer cells and spare healthy cells.
Furthermore, the Golgi apparatus in cancer cells is constitutively disassembled to accelerate protein trafficking and cell proliferation [14][15]. This fragmented Gogi is more sensitive to KIF20A inhibition.
EVX020, First-in-class selective KIF20A inhibitor
Originally identified[16] in partnership with the discoverers of anti-tubulin agents docetaxel and vinorelbine (ICSN, CNRS, Paris Saclay University), EVX020 (formerly DIACC2010) is a small molecule that selectively inhibits KIF20A, while preserving the activity of other related kinesins. After turning KIF20A off:
- Cytokinesis is blocked, leading to multinucleated cells and mitotic arrest (G2/M blockade).
- Secretion from the Golgi apparatus is blocked, leading to Golgi scattering and cell death (caspase activation and apoptosis induction).
EVX020 treatment leads to complete Golgi scattering and cell death in cancer cells
T24 bladder cancer cells were treated with EVX020 (100 nM, 50h) followed by IF analyses
Preclinical results
EVX020 exhibits high in vitro cytotoxic activity against a very large number of human cancer cell lines (IC50 in the 10-100 nM range). No cytotoxicity was observed on non-proliferative normal cells, such as primary hepatocytes and PBMC (IC50 > 50µM).
Tumor growth inhibition and survival increase were demonstrated in vivo in multiple hematologic and solid tumors, including AML & lymphoma, pancreatic / breast / colon / lung / bladder ca. models (i.v. injection at 200 mg/kg once a week).
Furthermore, target engagement (Golgi scattering) was confirmed in vitro and in vivo. [17][18].
Poster presented at ASH 2022
E-Poster presented at AACR2022
EVX020 development as a new payload for ADC
EVX020 clinical development has been plagued by formulation issues and the company intends to validate its potential as a potent, selective and safe molecule, with a broad spectrum of efficacy, that fits ideally as a new payload candidate for ADCs.
After having successfully completed the feasibility of conjugation and drug release with a conventional peptidic cleavable linker, the assessment of preclinical efficacy of ADC containing EVX020 as payload is ongoing, supported by innovation grant from Bpifrance, aiming to demonstrate superior efficacy and improved therapeutic index, as compared to marketed ADCs.