REPLACE: a route from PPI peptides to drug-like inhibitors

Rather than blocking ATP binding, PPI Pharmaceuticals targets protein-protein interactions that allosterically regulate kinase activity and other non-catalytic functions — interfaces long considered undruggable.

The problem

Cancer is second only to heart disease in total mortality.

The numbers

1.6M+

New U.S. cancer diagnoses / year

Cancer remains second only to heart disease in total mortality.

~500K

U.S. cancer deaths / year

Highlights the persistent need for better-targeted therapies.

~80K

Prostate patients needing better options

Approximate cohort cited for improved treatment need.

$100K+

Cost per course of treatment

FDA approved drugs can cost over $100,000/course of treatment

Estimated Incidence and Mortality of Common Cancers

Estimated incidence and mortality of common cancers
	Prostate / Breast		Lung		Colorectal
	Prostate / Breast Men	Prostate / Breast Women	Lung Men	Lung Women	Colorectal Men	Colorectal Women
Incidence	238,590(28%)	232,340(29%)	118,080(14%)	110,110(14%)	73,680(9%)	69,140(9%)
Mortality	29,720(10%)	39,620(15%)	87,260(28%)	72,220(26%)	26,300(9%)	24,530(9%)

U.S. estimates shown in the company overview for prostate, breast, lung, and colorectal cancers. Percentages are each figure’s share of all cancers for that sex.

World War I soldiers in a front-line trench, the setting in which mustard agents were first used — Many chemotherapy agents have been in use for decades and very toxic drugs.

Molecular model of an early chemotherapy agent — Many chemotherapy agents have been in use for decades and very toxic drugs.

Drug targets

Opening “undruggable” PPI space that traditional pharma left behind

Of roughly 5–10,000 potential drug targets in the human genome, traditional pharma typically focuses on highly druggable pockets — the low-hanging fruit. Higher-risk interfaces, including many protein-protein interactions, were long avoided for lack of methodology. The McInnes laboratory developed REPLACE to make more of these targets accessible to drug development.

SM targets
Highly druggable catalytic pockets — the low-hanging fruit traditional pharma already works on.
Biologics
Antibodies and related modalities covering a smaller set of extracellular targets.
“Undruggable”
The large remainder, including many protein-protein interfaces. This is where REPLACE is aimed.

Many companies pursue cancer drug development; high attrition (~99%) means the field needs multiple approaches. REPLACE uniquely positions PPI Pharmaceuticals against kinase PPI interfaces that ATP-site and biologic strategies do not fully cover.

The solution

A new era in cancer treatment

REPLACE converts peptidic protein-protein interaction determinants into selective oncology inhibitors.

Time magazine cover, 28 May 2001, on drugs that target tumors — Time, 28 May 2001

The REPLACE strategy

Structure-guided conversion of binding determinants

Map the PPI interface

Identify binding determinants from SAR, crystal structures, and substrate peptides that mediate allosteric or non-catalytic kinase functions.

Build FLIP / REPLACE libraries

Truncate peptide leads, select fragments by docking and scoring, and synthesize focused libraries that preserve critical contacts while shrinking molecular weight.

Optimize to drug-like inhibitors

Iterate N- and C-terminal caps, peptide minimization, and phosphomimetic design to yield selective, cell-active small molecules for preclinical models.

REPLACE scheme for the Cdc25c phosphosubstrate, from N-cap identification through N-cap and C-cap optimization and peptide minimization

Cyclin Groove Inhibitor Project

Letters A–D mark the path from a peptidic ligand, through fragment replacement, to a small-molecule inhibitor.

Panel A. Peptidic ligand bound at a protein-protein interface

Panel B. Fragment volume mapped onto the binding determinants

Panel C. Optimized ligand region highlighted on the interface

Panel D. Small-molecule inhibitor occupying the PPI site

PLK1 Polo Box Inhibitor Project

Polo-box domain inhibitors discovered through REPLACE, with Phase I STTR support for lead optimization, phenotypic analysis, drug-like property evaluation, and anti-tumor effects — including in vivo activity assessment in a prostate cancer model.

PLK1 polo-box inhibitor, with a callout from the binding site to a close-up of the same interaction

Aim 1: lead optimization of PBD inhibitors obtained through REPLACE.

Aim 2: phenotypic analysis, evaluation of drug-like properties, and anti-tumor effects, including determining in vivo activity in a prostate cancer model.

Tumor volume over 43 days of treatment for vehicle, BI2536, abiraterone, and the combination. — A. Tumor volume

Tumor weight for vehicle, BI2536, abiraterone, and the combination. — B. Tumor weight

Excised prostate tumors from vehicle, BI2536, abiraterone, and the combination groups. — C. Excised tumors

Serum PSA over 7 weeks for vehicle, BI2536, abiraterone, and the combination. — D. Serum PSA

In a prostate cancer model, PLK1-pathway inhibition combined with abiraterone reduced tumor volume, tumor weight, and serum PSA versus either agent alone.

BRAF Dimerization Inhibitor Project

Using targeted therapeutics, dramatic progress has been made in specific cancer types.
Others, including certain prostate, breast, and pancreatic tumors, can often have survival times measured in months.
Continued research into the molecular defects that cause cancer, and into metastasis, is key to future breakthroughs.

BRAF dimerization interface with labeled contact residues

BRAF inhibitor — targeted therapeutic

Resistance is a problem

Panel A. Clinical photographs before a targeted BRAF inhibitor, front and back — A

Panel B. Clinical photographs showing response to a targeted BRAF inhibitor, front and back — B

Panel C. Clinical photograph after relapse on a targeted BRAF inhibitor — C