First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer

Abstract

Since the discovery of CHD1L in 2008, it has emerged as an oncogene implicated in the pathology and poor prognosis of a variety of cancers, including gastrointestinal cancers. However, a mechanistic understanding of CHD1L as a driver of colorectal cancer has been limited. Until now, there have been no reported inhibitors of CHD1L, also limiting its development as a molecular target. We sought to characterize the clinicopathologic link between CHD1L and colorectal cancer, determine the mechanism(s) by which CHD1L drives malignant colorectal cancer, and discover the first inhibitors with potential for novel treatments for colorectal cancer. The clinicopathologic characteristics associated with CHD1L expression were evaluated using microarray data from 585 patients with colorectal cancer. Further analysis of microarray data indicated that CHD1L may function through the Wnt/TCF pathway. Thus, we conducted knockdown and overexpression studies with CHD1L to determine its role in Wnt/TCF-driven epithelial-to-mesenchymal transition (EMT). We performed high-throughput screening (HTS) to identify the first CHD1L inhibitors. The mechanism of action, antitumor efficacy, and drug-like properties of lead CHD1L inhibitors were determined using biochemical assays, cell models, tumor organoids, patientderived tumor organoids, and in vivo pharmacokinetics and pharmacodynamics. Lead CHD1L inhibitors display potent in vitro antitumor activity by reversing TCF-driven EMT. The best lead CHD1L inhibitor possesses drug-like properties in pharmacokinetic/pharmacodynamic mouse models. This work validates CHD1L as a druggable target and establishes a novel therapeutic strategy for the treatment of colorectal cancer.

Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome

“…More studies are needed to understand the in vivo effects. ALC1 is a promising target for cancer treatment, and small-molecule inhibitors targeting the ATPase activity have been found, although they showed low affinities 20 . In addition to the common strategy of inhibiting the ATPase activity, the sensitivity of the remodeling activity and the varied regulation modes of ALC1 provide rich opportunities and a large chemical space to control the function of this enzyme in cells.…”

“…ALC1 knockdown was shown to reverse tumor differentiation, abolish the malignant phenotypes, and increase the sensitivity of the HCC cells to chemotherapy. Small-molecule inhibitors of ALC1 exert potent antitumor activity by inhibiting the ATPase activity in colorectal cancer models 20 . ALC1 is indirectly blocked by PARP1 inhibitors, which have been used successfully in cancer treatment 10 , suggesting that the clinical benefits of these drugs may be partially attributable to their indirect effects on ALC1.…”

Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome

“…Recent studies have defined ALC1 as an attractive target for therapeutic intervention strategies in cancer as its inactivation sensitizes to clinical PARP inhibitors and confers synthetic lethality in homologous recombination-deficient cancer cells ( Abbott et al, 2020 ; Blessing et al, 2020 ; Hewitt et al, 2021 ; Juhász et al, 2020 ; Verma et al, 2021 ). However, despite thorough biochemical and biophysical scrutiny of its regulation and interaction with nucleosomes ( Ahel et al, 2009 ; Gottschalk et al, 2012 ; Gottschalk et al, 2009 ; Lehmann et al, 2020 ; Lehmann et al, 2017 ; Singh et al, 2017 ), ALC1 has so far resisted structure determination.…”

Diversity roles of CHD1L in normal cell function and tumorigenesis

“…PARP inhibitor Olaparib suppressed the DNA damage repair signaling and repressed the global pluripotent transcriptional network through CHD1L-mediated condensation of the chromatin structure in HCC [ 114 ]. Lead CHD1L inhibitors (Compounds 5–7) display potent antitumor activity by reversing TCF-driven EMT and induction of cleaved Ecadherin mediated extrinsic apoptosis in colorectal cancer [ 115 ]. The pharmacological inhibition of CHD1L might represent a promising therapeutic strategy for patients with decrease CHD1L expression.…”