2. Academic Validation
  3. Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

  • Bioorg Med Chem Lett. 2019 Apr 1;29(7):905-911. doi: 10.1016/j.bmcl.2019.01.036.
Birong Zhang 1,  James R Kiefer 2,  Robert A Blake 2,  Jae H Chang 2,  Steven Hartman 2,  Ellen Rei Ingalla 2,  Tracy Kleinheinz 2,  Vidhi Mody 2,  Michelle Nannini 2,  Daniel F Ortwine 2,  Yingqing Ran 2,  Amy Sambrone 2,  Deepak Sampath 2,  Maia Vinogradova 2,  Yu Zhong 2,  Jerome C Nwachukwu 3,  Kendall W Nettles 3,  Tommy Lai 4,  Jiangpeng Liao 4,  Xiaoping Zheng 4,  Hai Chen 4,  Xiaojing Wang 2,  Jun Liang 5
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: zhang.birong@gene.com.
  • 2 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3 Department of Integrated Structural and Computational Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
  • 4 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 5 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: liang.jun@gene.com.
PMID: 30732944 DOI: 10.1016/j.bmcl.2019.01.036
Abstract

Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+ breast Cancer continues to be a leading cause of Cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective Estrogen Receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective Estrogen Receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays.

Keywords

Constrained chromene; ERα; Estrogen receptor degrader; SERD.

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