Abstract 3043: CKAP2 modulation with a novel small molecule results in excellent <i>in-vitro</i> and <i>in-vivo</i> anti tumor activity

Abstract Cytoskeleton-Associated Protein 2 (CKAP2) is an intrinsically disordered protein, considered undruggable, and the most potent microtubule growth factor identified to date. It is associated with malignant progression, modulating multiple cancer-associated processes including cell proliferation, migration, metastasis and angiogenesis, and may act as a functional oncogene by targeting FAK-ERK2 signaling pathway. CKAP2 has been reported to be an important prognostic marker and potential therapeutic target in certain cancers (e.g. non-small cell lung cancer). We have discovered and are developing an oral CKAP2 small molecule modulator as a potential treatment for cancer. Bioinformatics analysis of a 300 tumor cell line panel treated with the CKAP2 modulator demonstrated a strong correlation between CKAP2 protein abundance and drug sensitivity across cancer types, with large B cell lymphoma and acute myeloid leukemia showing the highest drug sensitivity. Additionally, analysis in the TCGA cohort indicated that CKAP2 RNA expression was significantly elevated in patient tumors compared to normal tissues and strongly correlated with their predicted sensitivity to the CKAP2 modulator. Protein array analysis revealed that proteins associated with predicted sensitivity are involved in downstream pathways of CKAP2 such as cell migration and focal adhesion signaling. Functional studies indicated down-stream pathways of CKAP2 to be affected upon treatment. Treatment of cells with either the CKAP2 modulator, or with CKAP2 targeting siRNA, similarly decreased FAK protein level, reduced migration and diminished cell viability/count. Immunofluorescence-based assays confirmed altered CKAP2 phenotype and disruption of microtubule network upon treatment, resulting in G2/M cell cycle arrest. Furthermore, CKAP2 modulation significantly inhibited angiogenesis in tube formation assays using HUVECs and maintained activity in hypoxia, which is a driver of angiogenesis and associated with resistance to many therapies. In-vivo efficacy was demonstrated in a mouse xenograft model of non-small cell lung cancer and three different models of colon cancer with up to 79% tumor volume reduction noted at the highest dose tested and was well tolerated. In conclusion, we have discovered a first-in-class, oral small molecule which modulates CKAP2 and its downstream pathways indicating very good anti-tumor activity both in-vitro and in-vivo. This novel therapy is being considered as a promising therapeutic candidate for the treatment of CKAP2 expressing cancers. Citation Format: Deepa M. Sridharan, Vignesh Viswanathan, Dmitry Kuchenov, Quynh Mai, Yerem Yeghiazarians, Kurosh Ameri. CKAP2 modulation with a novel small molecule results in excellent in-vitro and in-vivo anti tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3043.