Targeting the “Undruggable” in Cancer Using Chemoproteomics-Enabled Covalent Ligand Discovery Platforms


ASPIRE AWARD (ASPIRE I: 2018-2019; ASPIRE II: 2020-PRESENT)

Daniel Nomura, PhD, University of California, Berkeley

Daniel Nomura, PhD

Small-molecule drugs that bind to specific target proteins and inhibit their function are a mainstay of precision cancer medicine. The development of therapies to target many proteins known to drive cancer has proven challenging, however, as over 90% of proteins are considered “undruggable” because they lack binding pockets where a small molecule can grab hold. In work funded by an ASPIRE Phase 1 grant from The Mark Foundation, researchers in the laboratory of Daniel Nomura at the University of California, Berkeley used activity-based protein profiling to discover new binding sites on target proteins, as well as covalent ligands that bind those sites. They now aim to expand this work to identify covalent ligands for additional cancer-relevant targets and develop effective cancer therapeutics based on the identified ligands. Molecules that impact target protein function can immediately enter the optimization process for developing a drug. Those that bind the target protein but are functionally ineffective can be converted into proteolysis targeting chimeras (PROTACs) by linking them to chemical structures that are known to recruit their targets to the cell’s protein degradation machinery. The Nomura group will also apply their chemoproteomic approach to expand beyond PROTACs to the discovery and development of a new class of therapeutics called induced proximity-based modalities (IPMs), which bring together proteins to restore normal cellular functions that have gone awry in cells or to create new functions that mitigate disease states. This project has the potential to both lay the foundation for the development of new cancer therapies and introduce new drug discovery paradigms that can be deployed in cancer and other diseases.

PUBLISHED RESEARCH

Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ, Nomura DK. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat Chem Biol. 2019.

Berdan CA, Ho R, Lehtola HS, To M, Hu X, Huffman TR, Petri Y, Altobelli CR, Demeulenaere SG, Olzmann JA, Maimone TJ, Nomura DK. Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells. Cell Chem Biol. 2019.

Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, Tong B, Maimone TJ, Zoncu R, Bassik MC, Nomura DK, Dixon SJ, Olzmann JA. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019.

Chung CY, Shin HR, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R, Nomura DK. Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nat Chem Biol. 2019.

Isobe Y, Okumura M, McGregor LM, Brittain SM, Jones MD, Liang X, White R, Forrester W, McKenna JM, Tallarico JA, Schirle M, Maimone TJ, Nomura DK. Manumycin polyketides act as molecular glues between UBR7 and P53. Nat Chem Biol. 2020.

Tong B, Spradlin JN, Novaes LFT, Zhang E, Hu X, Moeller M, Brittain SM, McGregor LM, McKenna JM, Tallarico JA, Schirle M, Maimone TJ, Nomura DK. A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL. ACS Chem Biol. 2020.

Boike L, Cioffi AG, Majewski FC, Co J, Henning NJ, Jones MD, Liu G, McKenna JM, Tallarico JA, Schirle M, Nomura DK. Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC. Cell Chem Biol. 2020.

Tong B, Luo M, Xie Y, Spradlin JN, Tallarico JA, McKenna JM, Schirle M, Maimone TJ, Nomura DK. Bardoxolone conjugation enables targeted protein degradation of BRD4. Sci Rep. 2020.

Luo M, Spradlin J, Boike L, Tong B, Brittain SM, McKenna JM, Tallarico JA, Schirle M, Maimone TJ, Nomura DK. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem. Biol. 2021.

Spradlin JN, Zhang E, Nomura DK. Reimagining Druggability Using Chemoproteomic Platforms. Acc Chem Res. 2021.

Belcher BP, Ward CC, Nomura DK. Ligandability of E3 Ligases for Targeted Protein Degradation Applications. Biochemistry. 2021.

Henning NJ, Manford AG, Spradlin JN, Brittain SM, Zhang E, McKenna JM, Tallarico JA, Schirle M, Rape M, Nomura DK. Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications. J Am Chem Soc. 2022.

Henning NJ, Boike L, Spradlin JN, Ward CC, Liu G, Zhang E, Belcher BP, Brittain SM, Hesse MJ, Dovala D, McGregor LM, Valdez Misiolek R, Plasschaert LW, Rowlands DJ, Wang F, Frank AO, Fuller D, Estes AR, Randal KL, Panidapu A, McKenna JM, Tallarico JA, Schirle M, Nomura DK. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat Chem Biol. 2022.

Page ACS, Scholz SO, Keenan KN, Spradlin JN, Belcher BP, Brittain SM, Tallarico JA, McKenna JM, Schirle M, Nomura DK, Toste FD. Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design. Chem Sci. 2022.

Boike L, Henning NJ, Nomura DK. Advances in covalent drug discovery. Nat Rev Drug Discov. 2022.

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