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About Amit Choudhary

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Proteolysis-targeting chimeras with reduced off-targets

Dec 18, 2023

Abstract Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation. Access options Get Nature+, our best-value online-access subscription $29.99 / 30 days $259.00 per year Prices vary by article type from$1.95 Additional access options: Fig. 2: Validation of image-based results using NanoBRET and immunoblotting. Fig. 3 Fig. 4: Synthesis of imide analogs using bromo- and amino- imide building blocks. Fig. 5: Degradation score as metric to nominate the imide analogues with reduced off-targets and cellular target engagement studies. Fig. 6: Validation of image-based platform by global proteomics. Fig. 7: Re-engineering of ALK PROTACs based on the design principles. Data availability Data generated in this study are provided in the manuscript, supplementary information and source data. The raw data corresponding to all the proteomics studies presented in this manuscript are available under the accession code PXD046264 . Plasmid from Addgene (plasmid 74450; www.addgene.org/74450/ ) was used in this study. Structural information from PDB (ID: 6H0F) was used in this study. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper. References Chamberlain, P. P. & Cathers, B. E. Cereblon modulators: low molecular weight inducers of protein degradation. Drug Discov. Today Technol. 31, 29–34 (2019). ImageJ user guide. (2012) NIH https://imagej.nih.gov/ij/docs/guide/ Meier, F. et al. diaPASEF: parallel accumulation–serial fragmentation combined with data-independent acquisition. Nat. Methods 17, 1229–1236 (2020). R Development Core Team (R Foundation for Statistical Computing, 2014). Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015). Acknowledgements We thank P. Byrne (Broad Institute) for assistance with automated imaging screening experiments. This work was supported by DARPA (N66001-17-2-4055) and NIH (R01 GM137606 and R01 GM132825 to A.C.; NIH CA214608 and CA218278 to E.S.F. ; R01 EB031172, R01 EB027793, and R35 GM118062 to D.R.L.). J.A.M.M. is a Ruth L. Kirchstein National Research Service Award Postdoctoral Fellow (F32 GM133088). D.R.L. and B.L.E. are investigators of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Author information Authors and Affiliations Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA Tuan M. Nguyen, Vedagopuram Sreekanth, Arghya Deb, Praveen Kokkonda, Praveen K. Tiwari, Veronika Shoba, Santosh K. Chaudhary, Sophia Lai, Ananthan Sadagopan & Amit Choudhary Department of Medicine, Harvard Medical School, Boston, MA, USA Tuan M. Nguyen, Vedagopuram Sreekanth, Arghya Deb, Praveen Kokkonda, Praveen K. Tiwari, Veronika Shoba, Santosh K. Chaudhary & Amit Choudhary Divisions of Renal Medicine and Engineering, Brigham and Women’s Hospital, Boston, MA, USA Tuan M. Nguyen, Vedagopuram Sreekanth, Praveen K. Tiwari & Amit Choudhary Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Katherine A. Donovan & Eric S. Fischer Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA Katherine A. Donovan & Eric S. Fischer Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA Jaron A. M. Mercer & David R. Liu Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA Jaron A. M. Mercer, Sophia Lai & David R. Liu Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA Jaron A. M. Mercer & David R. Liu Massachusetts Institute of Technology, Cambridge, MA, USA Ananthan Sadagopan Max Jan & Benjamin L. Ebert Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA Max Jan & Benjamin L. Ebert Howard Hughes Medical Institute, Boston, MA, USA Max Jan & Benjamin L. Ebert Authors Vedagopuram Sreekanth Arghya Deb Praveen Kokkonda Praveen K. Tiwari Katherine A. Donovan Veronika Shoba Santosh K. Chaudhary Jaron A. M. Mercer Sophia Lai Ananthan Sadagopan Max Jan Eric S. Fischer David R. Liu Benjamin L. Ebert Amit Choudhary

Amit Choudhary Investments

4 Investments

Amit Choudhary has made 4 investments. Their latest investment was in Kudos as part of their Angel on April 06, 2021.

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Amit Choudhary Investments Activity

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Date

Round

Company

Amount

New?

Co-Investors

Sources

4/6/2021

Angel

Kudos

Yes

1

6/12/2017

Seed

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$99M

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10

8/31/2016

Seed

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10

3/8/2016

Angel

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10

Date

4/6/2021

6/12/2017

8/31/2016

3/8/2016

Round

Angel

Seed

Seed

Angel

Company

Kudos

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Amount

$99M

New?

Yes

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Co-Investors

Sources

1

10

10

10

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