Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF

Mohammed S Abdel-Maksoud; Eslam M H Ali; Usama M Ammar; Karim I Mersal; Kyung Ho Yoo; Chang-Hyun Oh

doi:10.1016/j.bmc.2020.115493

Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting ^V600EBRAF

Bioorg Med Chem. 2020 Jun 1;28(11):115493. doi: 10.1016/j.bmc.2020.115493. Epub 2020 Apr 10.

Authors

Mohammed S Abdel-Maksoud¹, Eslam M H Ali², Usama M Ammar³, Karim I Mersal⁴, Kyung Ho Yoo⁵, Chang-Hyun Oh⁶

Affiliations

¹ Medicinal &Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC ID: 60014618), Dokki, Giza 12622, Egypt.
² Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University of Technology and Information (MTI), Cairo 12055, Egypt.
³ Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt.
⁴ Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea.
⁵ Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
⁶ Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea. Electronic address: choh@kist.re.kr.

PMID: 32340792
DOI: 10.1016/j.bmc.2020.115493

Abstract

Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved ^V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent ^V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their ^V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC₅₀ over ^V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC₅₀ values of 0.085 µM and 0.080 µM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.

Keywords: Anticancer; B-RAF inhibitors; Kinase inhibitor; Pyrrolo[2,3-b]pyridine; SAR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Pyrroles
BRAF protein, human
Proto-Oncogene Proteins B-raf
pyrrolo(2, 3-b)pyridine