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A new way to discover

Microbes and plants have been a rich source of cancer medicines such as camptothecin, taxol, auristatins, doxorubicin, and more. These blockbusters originated from a small fraction of the earth’s organisms. Advances in DNA sequencing have changed the landscape dramatically, revealing genes encoding those known medicines, as well as genes encoding many yet-unstudied molecules. Hexagon’s platform leverages these advances to unlock valuable molecules, particularly those directed at cancer.

Exploiting evolution’s chemistry for cancer treatments

The global metagenome – comprising millions of microbial and plant species – is a vast and largely unexplored territory for drug discovery.

 

Small molecules that evolved in nature are known as natural products. Many natural products target cancer-related proteins: for example, taxol evolved to stabilize microtubules, camptothecin evolved to inhibit topoisomerase-1, and doxorubicin evolved to inhibit topoisomerase-2. All of these molecules became FDA-approved drugs.

49% of small molecule cancer drugs and 73% of antibiotics originated from natural products.

Our platform

Groundbreaking technologies of the last decade including DNA sequencing, machine learning and synthetic biology have radically changed the opportunity. Mining these hidden compounds and leveraging them for cancer is suddenly possible.

Drug-Target Prediction

Our TICker algorithm computationally predicts microbial secondary metabolites that inhibit cancer-related proteins.

DNA Sequencing

We are building the world’s largest database of microbial genomes and metabolites, giving us ready access to diverse, unstudied chemicals

Compound Production

Our HEx platform produces novel compounds using heterologous expression, an approach that allows forced expression of the secondary metabolites of interest.

Solving for cancer

Many of the compounds produced by the earth’s biodiversity target core pathways implicated in cancer.

Antibody Drug Conjugates

The Hexagon platform, with its ability to discover evolutionarily refined molecules and their protein targets, is uniquely suited to discover new ADC payloads.

All current ADC payloads are derived from natural products.

Tubulin inhibitors

  • Monomethylauristatins: MMAE, MMAF (marine mollusk Dolabella auricularia)
  • Maytansine derivatives: DM1, DM4 (Ethiopian shrub Maytenus serrata)

DNA damage
(Break or Alkylation)

  • Calicheamicin (bacterium Micromonospora echinospora)
  • PBD (bacterium Streptomyces erythraeus)
  • Duocarmycins (bacterium Streptomyces sp)

DNA damage
(Topoisomerase-1 inhibition)

  • Camptothecin derivatives (Chinese tree Camptotheca acuminata)
Antibody Drug Conjugates in Oncology

Humans and microbes share ancient, growth-related genes, including some that are implicated in cancer. These include tubulin, topoisomerases, and DNA replication, which are the targets existing antibody drug conjugate (ADC) payloads used in cancer treatments today. All of these are based on natural products. Hexagon’s platform has identified other mechanisms and small molecules that evolved in nature and represent next-generation ADC payloads, spanning pathways such as cell cycle, transcription, translation, cytoskeleton, and more. This creates broad opportunities to discover and develop new small molecule approaches to treating patients with intractable cancers. Hexagon has found promising compounds which are being evaluated as novel payloads for ADCs.

Our proprietary genome database is expanding, with over 100,000 organismal strains banked, and over 80,000 genomes sequenced.

Our platform predicts several hundred potential ADC payload mechanisms of action, including DNA/RNA-associated pathways, energy production, protein-associated pathways, fat/lipid synthesis, and other cancer-related pathways.

Hexagon’s automated compound production systems are able to safely manufacture highly potent toxic natural products at production scales.

Hexagon is in the process of producing and characterizing several of these ADC payloads, focusing on those that present an opportunity to improve therapeutic response and overcome resistance observed to other payload classes.

1% of the world’s microbial genomes have been sequenced. Many existing blockbuster drugs were discovered here.

99% of microbial
genomes have yet to
be sequenced

Vast troves of new medicines are waiting to be surfaced.

Publications & Presentations

Inhibiting Protein Translation: A Novel ADC Payload With Strong Antitumor Activity in Mono- and Dual-Payload Formats

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

Tara Arvedson, Edres Babacarkhial, Cynthia Bailey, Nolan Carney, Xufeng Cao, Yi-Ming Chiang, Amber Cornelius, Madhura Deshpande, Kyle Dunbar, Natalie Duong, Amandeep Gakhal, Colin Harvey, Yingxia Hu, Dimitri Khrakovsky, Christopher Kimberlin, Jose Leighton Jr, Yu (Dennis) Liu, Luca Lizzadro, Octovia Monteiro, Samuel Oteng-Pabi, Bruno Perlatti, Corey Reeves, Rajani Marthappa Shenoy, Joseph Spraker, Mélanie Uguen, Jakub Vaith, Sandeep Venkataram, Kylie Wells, Kendra Wheeler, Shiyan Xu, Danielle Yee, Clarence Hue Lok Yeung, Bo (Eva) Yuan, Victor Cee, Natacha Le Moan

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Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules

Cell Chemical Biology

Thu P. Nguyen, Min Fang, Jiwoong Kim, Baiyun Wang, Elisa Lin, Vishal Khivansara, Neha Barrows, Giomar Rivera-Cancel, Maria Goralski, Christopher L. Cervantes, Shanhai Xie, Johann M. Peterson, Juan Manuel Povedano, Monika I. Antczak, Bruce A. Posner, Colin J.B. Harvey, Brian T. Naughton, David G. McFadden, Joseph M. Ready, Jef K. De Brabander, Deepak Nijhawan

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HEx: A heterologous expression platform for the discovery of fungal natural products.

Science Advances

Colin J. B. Harvey, Mancheng Tang, Ulrich Schlecht, Joe Horecka, Curt R. Fischer, Hsiao-Ching Lin, Jian Li, Brian Naughton, James Cherry, Molly Miranda, Yong Fuga Li, Angela M. Chu, James R. Hennessy, Gergana A. Vandova, Diane Inglis, Raeka S. Aiyar, Lars M. Steinmetz, Ronald W. Davis, Marnix H. Medema, Elizabeth Sattely, Chaitan Khosla, Robert P. St. Onge, Yi Tang, and Maureen E. Hillenmeyer.

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