Abstract 4495: TACC3 inhibition with KC1101 drives mitotic catastrophe and broad antitumor activity.

Abstract TACC3, an oncogenic member of the transforming acidic coiled-coil domain-containing protein (TACC) family, is a core component of multi-protein complexes regulating microtubule and centrosome-related processes. Aberrant overexpression of TACC3 is found across multiple cancers with centrosome instability and worse prognosis. Emerging evidence further highlights TACC3 as a therapeutic vulnerability, particularly in highly aggressive cancers characterized with centrosome amplification. We have profiled our selective TACC3 inhibitor -- KC1101 via cell proliferation assays across diverse cancer cell lines. KC1101 demonstrated potent anti-proliferative effects, approximately 2-fold more potent than AO-252, an oral TACC3 inhibitor currently in Phase I. Meanwhile, no cytotoxicity was observed in primary hepatocytes or PBMCs. Further studies indicated KC1101 triggered robust cell-cycle arrest at G2/M phase and markedly increased multipolar spindle formation, consistent with on-target disruption of TACC3-dependent spindle regulation. With once-daily oral dosing, KC1101 demonstrated superior antitumor activity in vivo across TNBC (MDA-MB-231, CAL-51) and colon (HCT116) xenograft models. At 20 mpk, KC1101 achieved 94.4% TGI in CAL-51 and 61.1% TGI in HCT-116, outperforming AO-252 (24.7% and 54.2%, respectively). Encouragingly, KC1101 also produced significant tumor suppression in an intracranial TNBC (MDA-MB-231-Luc) and AML (MOLM-13-Luc) model. All the data highlighted high therapeutic potential of KC1101. A wide safety margin in exploratory toxicology, coupled with low interspecies PK variability in mouse, rat, and dog, supports future clinical investigation. In conclusion, KC1101 delivers best-in-class potential for TACC3-addicted tumors by coupling strong mitotic-catastrophe biology with consistent, QD oral efficacy—including intracranial and hematologic settings—while avoiding primary-cell cytotoxicity. Collectively with the clinical precedent for TACC3 inhibition (AO-252), these data nominate KC1101 for IND in 2026. Citation Format: Lei Zhang, Xin Nie, Zhen Mi, Yin Guo, Xiaona Yang, Yinyin Zhang, Huaying Wang, Bingqian Li, Yong Peng, Yang Yang. TACC3 inhibition with KC1101 drives mitotic catastrophe and broad antitumor 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 4495.