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Maxam-Gilbert Sequencing

Maxam-Gilbert Sequencing

In the same year as the discovery of the Sanger sequencing method, another group of scientists, Allan Maxam and Walter Gilbert, demonstrated their chemical-cleavage method for DNA sequencing. The Maxam-Gilbert method relies on using different chemicals that can cleave the DNA sequence at specific sites, the separation of resulting DNA fragments of variable size using electrophoresis, and deciphering the DNA sequence from the resulting gel bands.
Challenges of the Maxam-Gilbert Method
The...

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Updated: Apr 6, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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Published on: October 26, 2015

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded

Koen F W Hekking¹, Sergio Maroto¹, Kees van Kekem¹

¹Symeres, 6546BB Nijmegen, The Netherlands.

Journal of Medicinal Chemistry

|February 2, 2024

Summary

Researchers developed novel macrocyclic compounds that inhibit myeloid cell leukemia 1 (Mcl-1), a protein linked to cancer growth and drug resistance. This approach offers a promising new avenue for developing targeted cancer therapies.

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Area of Science:

Medicinal Chemistry
Chemical Biology
Drug Discovery

Background:

Evasion of apoptosis is a hallmark of cancer, contributing to tumor development and growth.
Myeloid cell leukemia 1 (Mcl-1), a pro-survival protein in the Bcl-2 family, is implicated in tumor aggressiveness, poor prognosis, and resistance to therapies.
Targeting Mcl-1 often involves inhibiting protein-protein interactions, which typically requires complex, large molecules and extensive optimization.

Purpose of the Study:

To develop novel, potent inhibitors of Mcl-1 using an innovative drug discovery approach.
To generate conformationally constrained macrocyclic compounds as Mcl-1 inhibitors.
To identify lead candidates with optimized potency and favorable physicochemical properties for therapeutic development.

Main Methods:

Utilized DNA-encoded chemical library synthesis and screening to identify initial hit compounds.
Employed a combination of conformational analysis and structure-based design for optimization.
Leveraged a robust synthetic platform for rapid analoging and property fine-tuning.

Main Results:

Successfully generated complex, conformationally privileged macrocyclic Mcl-1 inhibitors.
Optimized the in vitro potency of a lead series to the low nanomolar range.
Identified lead candidates (compounds 57/59) with a balanced profile of potency and physicochemical properties.

Conclusions:

DNA-encoded chemical libraries combined with structure-based design provide an efficient route to complex macrocyclic inhibitors.
The identified macrocyclic compounds represent promising lead candidates for Mcl-1 targeted cancer therapy.
These findings pave the way for further preclinical development of novel anti-cancer agents.