Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase

  • J Med Chem. 2024 Nov 14;67(21):19736-19754. doi: 10.1021/acs.jmedchem.4c02083.
Jennifer X Qiao  1 ,  David Williams  1 ,  Patrice Gill  1 ,  Ling Li  1 ,  Derek Norris  1 ,  John S Tokarski  2 ,  Jessica Wong  3 ,  Huilin Qi  3 ,  Yamnah Hafeji  3 ,  Daniel P Downes  4 ,  Bill Degnen  4 ,  Ying-Kai Wang  4 ,  Gregory Locke  4 ,  Hua Fang  4 ,  Fei Yu  4 ,  Songmei Xu  4 ,  Joseph Naglich  4 ,  Jun Zhang  4 ,  Purushothama Nanjappa  5 ,  Chao Dai  5 ,  Lisa Chourb  6 ,  Jonathan Napoline  6 ,  Richland Tester  7 ,  Christine Jorge  7 ,  Yi-Xin Li  7 ,  Arvind Mathur  7 ,  Christopher Barbieri  4 ,  Matthew G Soars  6 ,  Avinashnarayan Venkatanarayan  3 ,  Emma Lees  3 ,  Robert M Borzilleri  1 ,  Ashvinikumar V Gavai  1 ,  Michael Wichroski  3 ,  T G Murali Dhar  1
Affiliations
  • 1. Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
  • 2. Molecular Structure & Design, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
  • 3. Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States.
  • 4. Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
  • 5. Discovery Pharmacology and in vivo Biology, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States.
  • 6. Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States.
  • 7. Department of Discovery Synthesis, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
PMID: 39437163 DOI: 10.1021/acs.jmedchem.4c02083
Abstract

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 39. LDD 39 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, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. 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 39 at 15 and 75 mg/kg, respectively.

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