Biology subjects

Nijhawan, D.

Publications and source records attributed to Nijhawan, D..

4 recordsLinked to original sources

bioRxiv2025

A small molecule inhibitor of NVL suppresses tumor growth by blocking ribosome biogenesis

A longstanding hypothesis, stemming from the enlarged nucleoli typical of cancer cells, posits ribosome production as a selective cancer liability. Certain genotoxic chemotherapies work partly by disrupting ribosome biogenesis, highlighting the need for selective inhibitors of this pathway. Using forward genetics, we identified mutations in the essential 60S ribosomal subunit assembly factor NVL that confer resistance to MM17, a dibenzothiazepinone with anticancer activity. Cryo-EM reconstructions of the NVL hexameric assembly reveal two MM17 docking sites adjacent to resistance mutations. NVL inhibition by MM17 arrests 60S biogenesis in the nucleolus and induces cell cycle arrest or apoptosis through both MDM2/p53-dependent and p53-independent pathways, without causing DNA damage. A bioavailable analog, MM927, suppresses tumor growth in mouse models of leukemia and colorectal cancer without observable toxicity. These findings establish NVL inhibitors as a promising new class of targeted therapeutics and validate ribosome biogenesis as a cancer-specific vulnerability.

biochemistry↗

bioRxiv2025

Attention Guided Mechanism Interpretable Drug-Gene Interaction (MIDI) Modeling for Cancer Drug Response Prediction and Target Effect Explanation

Cancer drug discovery using genetic information is still poorly developed. Precisely locating drug atoms and explaining the targeting effect is crucial in precision medicine since it helps understand the drugs mechanism of action. Much data has been collected regarding drug response against cancer cell lines, and many models predict the drug response based on genomic information. However, to our knowledge, none of the data-driven techniques propose to detect the targeting mechanism of small drug molecules against genetic targets. In this work, we propose MIDI (Mechanism Interpretable Drug-Gene Interaction) model to delve deep into the targeting relation between drug molecules against genetic patterns. We show that purely based on a data-driven approach, the attention mechanism in our model could capture the important binding effect of small molecules towards gene targets. We provide both theoretical derivation and experiment results to show the information flow regarding the attention mechanism. In the meantime, we demonstrate that our model presents much higher prediction performance with the interpretation mechanism than the other state-of-the-art drug response prediction models.

cancer biology↗

bioRxiv2023

Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules

Orphan cytotoxins are small molecules for which the mechanism of action (MoA) is either unknown or ambiguous. Unveiling the mechanism of these compounds may lead to useful tools for biological investigation and in some cases, new therapeutic leads. In select cases, the DNA mismatch repair-deficient colorectal cancer cell line, HCT116, has been used as a tool in forward genetic screens to identify compound-resistant mutations, which have ultimately led to target identification. To expand the utility of this approach, we engineered cancer cell lines with inducible mismatch repair deficits, thus providing temporal control over mutagenesis. By screening for compound resistance phenotypes in cells with low or high rates of mutagenesis, we increased both the specificity and sensitivity of identifying resistance mutations. Using this inducible mutagenesis system, we implicate targets for multiple orphan cytotoxins, including a natural product and compounds emerging from a high-throughput screen, thus providing a robust tool for future MoA studies.

biochemistry↗

bioRxiv2019

Structural basis of recruitment of RBM39 to DCAF15 by a sulfonamide molecular glue E7820

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. In order to understand their mechanism of action, we carried out kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the 1 helix of RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other protein of interests.

biophysics↗