phosphatase inhibitors | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Posts Tagged ‘phosphatase inhibitors’

New Drugs on the Horizon: Part 3
Introduction

Andrew J. Phillips, C4 Therapeutics

symposium brought by AACR CICR and had about 30 proposals for talks and chose three talks
unfortunately the networking event is not possible but hope to see you soon in good health

ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies

T-cell receptors (TCR) can recognize the intracellular targets whereas antibodies only recognize the 25% of potential extracellular targets
survivin is expressed in multiple cancers and correlates with poor survival and prognosis
CD3 bispecific TCR to survivn (Ab to CD3 on T- cells and TCR to survivin on cancer cells presented in MHC Class A3)
ABBV184 effective in vivo in lung cancer models as single agent;
in humanized mouse tumor models CD3/survivin bispecific can recruit T cells into solid tumors; multiple immune cells CD4 and CD8 positive T cells were found to infiltrate into tumor
therapeutic window as measured by cytokine release assays in tumor vs. normal cells very wide (>25 fold)
ABBV184 does not bind platelets and has good in vivo safety profile
First- in human dose determination trial: used in vitro cancer cell assays to determine 1st human dose
looking at AML and lung cancer indications
phase 1 trial is underway for safety and efficacy and determine phase 2 dose
survivin has very few mutations so they are not worried about a changing epitope of their target TCR peptide of choice

The discovery of TNO155: A first in class SHP2 inhibitor

Matthew J. LaMarche
Novartis @Novartis

SHP2 is an intracellular phosphatase that is upstream of MEK ERK pathway; has an SH2 domain and PTP domain
knockdown of SHP2 inhibits tumor growth and colony formation in soft agar
55 TKIs there are very little phosphatase inhibitors; difficult to target the active catalytic site; inhibitors can be oxidized at the active site; so they tried to target the two domains and developed an allosteric inhibitor at binding site where three domains come together and stabilize it
they produced a number of chemical scaffolds that would bind and stabilize this allosteric site
block the redox reaction by blocking the cysteine in the binding site
lead compound had phototoxicity; used SAR analysis to improve affinity and reduce phototox effects
was very difficult to balance efficacy, binding properties, and tox by adjusting stuctures
TNO155 is their lead into trials
SHP2 expressed in T cells and they find good combo with I/O with uptick of CD8 cells
TNO155 is very selective no SHP1 inhibition; SHP2 can autoinhibit itself when three domains come together and stabilize; no cross reactivity with other phosphatases
they screened 1.5 million compounds and got low hit rate so that is why they needed to chemically engineer and improve on the classes they found as near hits