WDHD1

Last update 08 May 2025

Basic Info

Synonyms

Acidic nucleoplasmic DNA-binding protein 1, AND-1, AND1

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Introduction

Core replisome component that acts as a replication initiation factor. Binds directly to the CMG complex and functions as a hub to recruit additional proteins to the replication fork.

100 Clinical Results associated with WDHD1

100 Translational Medicine associated with WDHD1

0 Patents (Medical) associated with WDHD1

160

Literatures (Medical) associated with WDHD1

31 Dec 2024·Journal of Enzyme Inhibition and Medicinal Chemistry

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells

Article

Author: Hou, Wenbin ; Zhang, Yunze ; Chen, Leyuan ; Ren, Zhonghao ; Li, Yiliang

Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance in vitro and in vivo. However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, A15 with a "V" conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of A15 significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.

04 Nov 2024·Molecular Cancer Therapeutics

Identification of ATP-Competitive Human CMG Helicase Inhibitors for Cancer Intervention that Disrupt CMG-Replisome Function

Article

Author: Lawrence, Harshani R. ; Reed, Damon R. ; Luo, Xingju ; Craig, Kendall C. ; Alexandrow, Mark G. ; Ferreira, Renan B. ; Welch, Darcy L. ; Lawrence, Nicholas J. ; Xiang, Shengyan

AbstractThe human CMG helicase (Cdc45-MCM-GINS) is a novel target for anticancer therapy. Tumor-specific weaknesses in the CMG are caused by oncogene-driven changes that adversely affect CMG function, and CMG activity is required for recovery from replicative stresses such as chemotherapy. Herein, we developed an orthogonal biochemical screening approach and identified CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure–activity information, in silico docking, and testing with synthetic chemical compounds indicate that CMGi require specific chemical elements and occupy ATP-binding sites and channels within minichromosome maintenance (MCM) subunits leading to the ATP clefts, which are likely used for ATP/ADP ingress or egress. CMGi are therefore MCM complex inhibitors (MCMi). Biologic testing shows that CMGi/MCMi inhibit cell growth and DNA replication using multiple molecular mechanisms distinct from other chemotherapy agents. CMGi/MCMi block helicase assembly steps that require ATP binding/hydrolysis by the MCM complex, specifically MCM ring assembly on DNA and GINS recruitment to DNA-loaded MCM hexamers. During the S-phase, inhibition of MCM ATP binding/hydrolysis by CMGi/MCMi causes a “reverse allosteric” dissociation of Cdc45/GINS from the CMG that destabilizes replisome components Ctf4, Mcm10, and DNA polymerase-α, -δ, and -ε, resulting in DNA damage. CMGi/MCMi display selective toxicity toward multiple solid tumor cell types with K-Ras mutations, targeting the CMG and inducing DNA damage, Parp cleavage, and loss of viability. This new class of CMGi/MCMi provides a basis for small chemical development of CMG helicase-targeted anticancer compounds with distinct mechanisms of action.

01 Nov 2024·Developmental Dynamics

Transcriptional regulators with broad expression in the zebrafish spinal cord

Article

Author: Fancher, William F. ; Campbell, Paul C. ; Grieb, Ginny ; Banerjee, Santanu ; Lewis, Katharine E. ; England, Samantha J. ; Bates, Richard L.

AbstractBackgroundThe spinal cord is a crucial part of the vertebrate CNS, controlling movements and receiving and processing sensory information from the trunk and limbs. However, there is much we do not know about how this essential organ develops. Here, we describe expression of 21 transcription factors and one transcriptional regulator in zebrafish spinal cord.ResultsWe analyzed the expression of aurkb, foxb1a, foxb1b, her8a, homeza, ivns1abpb, mybl2b, myt1a, nr2f1b, onecut1, sall1a, sall3a, sall3b, sall4, sox2, sox19b, sp8b, tsc22d1, wdhd1, zfhx3b, znf804a, and znf1032 in wild‐type and MIB E3 ubiquitin protein ligase 1 zebrafish embryos. While all of these genes are broadly expressed in spinal cord, they have distinct expression patterns from one another. Some are predominantly expressed in progenitor domains, and others in subsets of post‐mitotic cells. Given the conservation of spinal cord development, and the transcription factors and transcriptional regulators that orchestrate it, we expect that these genes will have similar spinal cord expression patterns in other vertebrates, including mammals and humans.ConclusionsOur data identify 22 different transcriptional regulators that are strong candidates for playing different roles in spinal cord development. For several of these genes, this is the first published description of their spinal cord expression.

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WDHD1

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