Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase
We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound <b>39</b>. LDD <b>39</b> demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, <b>39</b> exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound <b>3</b>. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD <b>39</b> at 15 and 75 mg/kg, respectively.
Authors
- R. M. Borzilleri
- Ashvinikumar V. Gavai (ORCID: https://orcid.org/0000-0002-6067-4176)
- Yamnah A. Hafeji
- Michael Wichroski (ORCID: https://orcid.org/0009-0009-2664-2347)
- Ying-Kai Wang
- Christopher M. Barbieri (ORCID: https://orcid.org/0000-0002-3266-0201)
- John S. Tokarski
- Derek Norris
- Songmei Xu
- Emma Lees
- Chao Dai (ORCID: https://orcid.org/0009-0007-0701-0059)
- Patrice Gill
- Richland Tester
- Purushothama Nanjappa
- T. G. Murali Dhar (ORCID: https://orcid.org/0000-0003-0738-1021)
- J. Wesley Napoline
- Matthew G. Soars
- Daniel P. Downes (ORCID: https://orcid.org/0000-0002-6037-4501)
- Lisa Chourb
- Jennifer X. Qiao (ORCID: https://orcid.org/0000-0002-6685-2092)
- Gregory Locke
- Christine Jorge (ORCID: https://orcid.org/0009-0008-0536-9727)
- Avinashnarayan Venkatanarayan (ORCID: https://orcid.org/0000-0002-0175-6331)
- Joseph G. Naglich
- Ling Li (ORCID: https://orcid.org/0000-0002-0087-3034)
- Yixin Li (ORCID: https://orcid.org/0000-0002-9286-1187)
- Hua Fang (ORCID: https://orcid.org/0000-0003-1235-647X)
- Arvind Mathur (ORCID: https://orcid.org/0000-0002-7702-4006)
- David Williams
- Jessica Wong
- Fei Yu (ORCID: https://orcid.org/0000-0003-4367-2707)
- Huilin Qi
- Bill Degnen
- Jun Zhang (ORCID: https://orcid.org/0000-0002-3067-2620)
Institutions
- Bristol-Myers Squibb (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02083
- Citations
- 6
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 1.70