MECHANISM OF ACTION & KEY DATA

APIM Therapeutics is developing a pipeline of peptide compounds engineered to penetrate cells and target PCNA in both nucleus and the cytoplasm. ATX-101, the company’s current lead compound, is a first-in-class, chemically synthesized peptide targeting PCNA/APIM interactions formed upon DNA Damage Response. ATX-101 acts at three different levels:

  1. Blocking the DNA Damage Response in response to cytotoxic drugs (blocking key DNA repair pathways
  2. Prevention of secondary mutations induced by cytotoxic drugs (by blocking Translesion Synthesis, TLS)
  3. Targeting DDR-activated signaling pathways that protect cancer from genomic instability and promote resistance/escape

ATX-101 is currently being developed for the treatment of several cancer indications either alone or in combination with selected anti-cancer agents. The drug pipeline of APIM Therapeutics is presented below. ATX-101's clinical development program will comprise a phase I/IIa study in non-muscle invasive bladder cancer (intravesical administration) and a phase I/IIa study in advanced cancer patients (intravenous administration). Both studies are planned within 2016.

 Drug Pipeline

Based on this mechanism of action, APIM-peptides are predicted to improve the therapeutic index of existing therapies by:

  1. Increasing the efficacy of current anti-cancer agents without a concomitant rise in toxicity and
  2. Re-establishing pharmacological sensitivity to resistant cancers.

 

 

 

 

Key Data
ATX-101 shows single agent activity in various cancer lines including Bladder, Breast, Multiple Myeloma, Acute Myeloid Leukemia and in Lung, Prostate and Pancreatic cancer cells (among others).

Furthermore, ATX-101 increases the efficacy of a series of agents, including, among others, interstrand crosslinkers, intercalating agents, cancer antibiotics, stress-inducing and molecular targeted agents (e.g. p38, MAPK, EGFR inhibitors and others). In vivo, ATX-101 has shown proof-of-concept in blood and solid tumor animal models in combination with several clinically relevant drugs. Finally, ATX-101 shows strong anti-cancer action in myeloma patient-derived bone marrow samples ex vivo.

Overall, ATX-101 shows a strong combinatorial capacity in vitro and in vivo.

About PCNA
PCNA is currently recognized as a "hub" protein interacting with a wide network of proteins involved in the DNA Damage Response (e.g. proteins involved in DNA repair, chromatin remodeling/ epigenetic & cell cycle control, signal transduction and apoptosis). During normal replication, proteins which facilitate replication interact with PCNA through a peptide sequence known as the PIP-box. However, under conditions of DDR stress, there is a switch in the affinity of proteins interacting with PCNA from those which, under normal conditions, interact via the PIP-box motif to those involved in coping with stress through an interaction via the APIM motif. Via this "stress-switch" response, PCNA ultimately controls cellular responses to several stress inducing agents including a wide range of chemotherapeutic and targeted agents.

About APIM-motif
The APIM-motif is present in a large number of proteins involved in the DNA Damage Response (e.g. in genome maintenance, cell cycle control and signal transduction). By incorporating the APIM motif in a peptide drug, several cellular defense systems dealing with stress are simultaneously impaired. This results in hypersensitivity to many anti-cancer treatments as well as induction of rapid apoptosis in cancer cells treated with APIM-peptides as single agents.