A snapshot of target innovation in 2020

An analysis of BioCentury’s Distillery captures trends from preclinical publications in 2020

By Karen Tkach Tuzman, Senior Editor

January 1, 2021 1:37 AM UTC

Preclinical publications highlighted in BioCentury’s Distillery this year identified white space target opportunities including untapped E3 ubiquitin ligases, vesicular regulators and ion channels, as well as new indications and technologies for targets already flagged by industry.

BioCentury’s Distillery, a curated collection of top translational studies in the scientific literature, provides summaries of preclinical papers showing innovative interventions with disease-modifying effects.

An analysis cross-referencing 164 papers captured by the Distillery in 2020 to the competitive landscape reflected in BioCentury’s BCIQ database identified 78 studies featuring targets not represented in any disclosed, active company programs.

These white space targets include new entrants into hot target categories such as E3 ligases, which are a big focus for the next-generation of targeted protein degraders.

And while the explosive boom in COVID-19 studies dominated the headlines, researchers also found new inroads into other infectious diseases, some via host targets.

Other studies described new opportunities for known cancer targets outside of oncology, or therapeutic modalities that could have advantages over company programs against targets long linked to specific cancers or hereditary diseases.

Sampling innovation

BioCentury’s editorial team selects 10-15 papers per month from a survey of about 30 journals, prioritizing studies that identify new target opportunities or overcome hurdles faced by existing technologies addressing established targets.

The summaries distill each study down to its most translationally relevant experiments and conclusions, and include information on the innovation’s patent and licensing status when available.

The Distillery is also curated to enrich for licensing opportunities, meaning studies from academic labs and small companies are prioritized over those from companies more likely to develop programs themselves. It emphasizes original application of targets — papers on compounds already in the clinic are not included unless the use-case or disease is novel.

The Distillery also lists corresponding authors, allowing licensees to contact innovators, as well as bibliographic information on the original study.

Cancer dominates among this year’s disease categories, reflecting research funding investment in oncology compared with other therapeutic areas.

The next-most covered areas are infectious disease and neurology, two spaces that pharmas have considered risky in recent years, though the former has seen a resurgence due to the coronavirus pandemic, and the latter has seen a jump in investment over the past three years on the back of target de-risking strategies and new modalities.

Roads less traveled

Among the new targets described in papers published over the past year were those that could counteract infections by parasites, fungi and bacteria.

Pathogenic targets included two kinases used by parasitic flatworms, a stress response protein driving drug resistance in Candida, biofilm regulators for Salmonella, and a vaccine antigen for African sleeping sickness.

Host-targeting strategies for infectious diseases were also represented, including membrane protein targets for malaria and the Gram-positive bacteria Paeniclostridium sordellii.

Yale University researchers filed a patent application for the African sleeping sickness vaccine, and a University of Toronto team including Leah Cowen and Luke Whitesell, co-founders of antifungal company Bright Angel Therapeutics Inc., said its unpatented YCK2 inhibitor is available for licensing.

Not surprisingly, coronaviruses dominated the list of infectious disease articles in the Distillery this year, though these five studies represent only a tiny fraction of the product development activity brought on by COVID-19. BioCentury captured the bulk of coronavirus programs in development, including vaccines, antivirals, and immune-targeting therapies, in its COVID-19 Resource Center.

While companies in the targeted degradation space have declined to disclose which new E3 ligases they are eyeing, a spate of papers published in Nature Communications in 2020 described targeting strategies for E3 ligases not disclosed in any company programs. Three are active in cancer, and another plays a role in Middle East respiratory syndrome (MERS).

The St. Jude Children’s Research Hospital researchers who published on the oncogenic E3 ubiquitin ligase MAGEA11 told BioCentury their next steps include developing small molecule inhibitors of MAGE proteins, and incorporating cancer-specific ubiquitin ligases into targeted protein degraders.

Another white space target category that emerged in the 2020 Distillery was proteins that control vesicular functions in cells, including endocytosis, vesicular trafficking, lysosomal degradation, Golgi function and the regulation of endoplasmic reticulum (ER) cargo.

Translational applications for these targets included cardiovascular disease, oncology, neurology and rare diseases.

Patented innovations available for licensing or partnering include a RAB22A-blocking strategy from a Sun Yat-Sen University team, and the combination of DMN inhibitor prochlorperazine with mAb therapies for cancer from University of Queensland in Australia.

The safety dose-escalation Phase Ib CESTEM-I trial of prochlorperazine plus cetuximab for metastatic head and neck squamous cell carcinoma cell (SCC) and triple-negative breast cancer (TNBC) has been completed; next steps include a Phase II trial.

Disease-modifying experiments involving ion channels represent a source of candidate targets for neurology.

The indications with ion channel targets published in 2020 include stroke, epilepsy, pain and the neurological symptoms of systemic lupus erythematosus (SLE).

Two compounds that could treat stroke — a cell-penetrating peptide from a University of Pittsburgh team targeting potassium channel KCNB1, and a small molecule developed by a Heidelberg University team that disrupts interactions between TRPM4 and GRIN2A — have patent applications filed, and are available for licensing or partnering.

Stroke was the leading neurology indication. Papers addressing rare or multiple neurology indications make up the next largest category, followed by Alzheimer’s disease.

Studies in the Distillery pinpointed a set of lipid-modifying enzymes with translational potential, including a ceramide hydrolase, palmitoylating and de-palmitoylating enzymes, a β oxidation enzyme, and a lipid deacetylase.

The University of California San Francisco team behind an ASAH1 inhibition strategy for liver fibrosis and non-alcoholic steatohepatitis (NASH) declined to disclose the patent status of their technology, but said it was available for licensing.

New directions for established targets

Studies covered in the Distillery found emerging opportunities for industry targets in new indications, particularly in the case of targets that have already found a foothold in cancer.

Repurposed targets include receptor tyrosine kinase ROR2, serine protease FAP, anti-apoptotic protein MCL1, pro-inflammatory cytokine IL18R1, transcription elongation regulator CDK12, and low-density lipoprotein receptor LRP1.

The new indications spanned neurology, musculoskeletal diseases and metabolic disorders.

Patent applications have been filed for the ROR2, CDK12, LRP1 and MCL1 programs.

The ROR2 program from Queen Mary University of London is available for licensing or partnering, while the licensing statuses of the latter three — respectively from University of Nottingham, University of California Santa Barbara and a team from Harvard Medical School, Taizhou University and Zhejiang University School of Medicine — are undisclosed.

Among the studies that focused on cancer itself, solid tumors predominated, with colorectal cancer, breast cancer, melanoma and brain cancer taking the top spots. The hematological cancer covered most frequently was acute myelogenous leukemia (AML).

The Distillery also includes papers describing new technologies that could better address known relationships between targets and disease.

In 2020, that included antisense oligos (ASOs) targeting DUX4 for muscular dystrophy and CLN3 for Batten disease, in vivo base editing of the TERT promoter for brain cancer, ex vivo CRISPR editing strategies to increase fetal hemoglobin production in sickle cell disease and CFTR function in cystic fibrosis, and a cell-penetrating peptide and RNA-binding small molecule targeting FMR1 for Fragile X syndrome and α synuclein for Parkinson’s disease.

The DUX4 ASOs from University of Alberta and The George Washington University, and the TERT promoter editing approach from Chinese Academy of Sciences, have patent applications filed and are available for licensing and partnering.

A patent application has also been filed for the FMR1 peptide therapy from University of Calgary, and the SCNA mRNA-binding compound from Rutgers University is available for licensing; its patent status is undisclosed.

Geographic view

Corresponding authors of papers featured in the Distillery were predominantly based in the U.S.

China, Japan and South Korea are the three leading sources of Distillery papers from Asian countries, while Belgium, Germany and the U.K. are the top three sources of studies from Europe. Australia and Canada join Germany, the U.K. and the U.S. to round out the top five.

TARGETS
3 DLG3 (SAP102; MRX; XLMR) - Discs large MAGUK scaffold protein
AADAC (DAC) - Arylacetamide deacetylase
AQP3 (GIL) - Aquaporin-3
ASAH1 - N-acylsphingosine amidohydrolase 1
BECN1 (ATG6) - Beclin 1
C. albicansYCK2 - Candida albicans serine/threonine protein kinase YCK2
CDK12 - Cyclin dependent kinase 12
CFTR - Cystic fibrosis transmembrane conductance regulator
CLN3 - Ceroid-lipofuscinosis neuronal 3
DECR1 (DECR; SDR18C1) - 2,4-dienoyl-CoA reductase 1
DMN - Dynamin
DUX4 - Double homeobox 4
FAP - Fibroblast activation protein
FMR1 (FMRP) - Fragile X mental retardation 1
GRIN2A (NR2A) - NMDA receptor NR2A subtype
HBG1 - Hemoglobin subunit gamma 1
HBG2 - Hemoglobin subunit gamma 2
IL18R1 (CD218a; IL18RA; IL-18Ralpha) - Interleukin-18 receptor 1
IRE1 (ERN1; IRE1A) - Endoplasmic reticulum to nucleus signaling 1
KCNB1 - Potassium channel Kv2.1
KCNJ3 (GIRK1) - Potassium channel Kir3.1
LAMP2 (LAMPB; CD107b) - Lysosomal-associated membrane protein-2
LRP1 (CD91) - Low-density lipoprotein-related protein 1 alpha-2-macroglobulin receptor
LYPLA2 - Lysophospholipase 2
MAGEA11 - MAGE family member A11
MCL1 - Myeloid leukemia cell differentiation protein
P. sordellii TcsL - Paeniclostridium sordellii cytotoxin L
PCF11 - PCF11 cleavage and polyadenylation factor subunit
RAB22A - RAB22A member RAS oncogene family
RAP1GDS1 - Rap1 GTPase-GDP dissociation stimulator 1
RNF208 - Ring finger protein 208
ROR2 - Receptor tyrosine kinase-like orphan receptor 2
S. entericacsgA - Salmonella enterica curli major subunit
S. entericacsgB - Salmonella enterica curli minor subunit
SEMA6A - Semaphorin 6A
SEMA6B - Semaphorin 6B
SKP2 - S-phase kinase-associated protein 2
SNCA- Alpha synuclein
SNPH - Syntaphilin
SURF4 - Surfeit 4
STK25 - Schistosoma mansoni Serine/threonine kinase 25
STX5 - Syntaxin 5
T. brucei brucei SGM1.7 (Tb927.7.6600) - Trypanosoma brucei bruceisalivary gland metacyclic protein 1.7
TAOK1 - Schistosoma mansoni TAO kinase 1
TERT - Telomerase reverse transcriptase
TMEM120A (NET29; TMPIT) - Transmembrane protein 120A
TRIM25 - Tripartite motif containing 25
TRPM4 - Transient receptor potential cation channel subfamily M member 4
VAPA (VAP-A; VAP33; VAP-33) - VAMP associated protein A
ZBTB7A (LRF) - Zinc finger and BTB conatining 7A
ZDHHC7 - Zinc finger DHHC-type containing 7