2. Academic Validation
  3. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1)

Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1)

  • J Med Chem. 2020 Dec 10;63(23):14522-14529. doi: 10.1021/acs.jmedchem.0c00978.
Toufike Kanouni 1,  Christophe Severin 2,  Robert W Cho 3,  Natalie Y-Y Yuen 4,  Jiangchun Xu 2,  Lihong Shi 2,  Chon Lai 2,  Joselyn R Del Rosario 2,  Ryan K Stansfield 5,  Lee N Lawton 6,  David Hosfield 7,  Shawn O'Connell 8,  Matt M Kreilein 9,  Paula Tavares-Greco 9,  Zhe Nie 10,  Stephen W Kaldor 1,  James M Veal 5,  Jeffrey A Stafford 5,  Young K Chen 2
Affiliations

Affiliations

  • 1 Fount Therapeutics, LLC, San Diego, California 92130, United States.
  • 2 Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
  • 3 Quanticel Pharmaceuticels, San Francisco, California 94158, United States.
  • 4 Oric Pharmaceuticals, South San Francisco, California 94080, United States.
  • 5 858 Therapeutics, Inc., San Diego, California 92121, United States.
  • 6 Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 7 University of Chicago, Chicago, Illinois 60637, United States.
  • 8 Pfizer Inc., San Diego, California 92121, United States.
  • 9 Bristol Myers Squibb, Summit, New Jersey 07901, United States.
  • 10 Schrödinger, Inc., San Diego, California 92121, United States.
PMID: 33034194 DOI: 10.1021/acs.jmedchem.0c00978
Abstract

Histone Demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a Cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung Cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).

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