Delving into the Latest Updates on Xpose Therapeutics, Inc. with Synapse

Overview

Tags

Neoplasms

Small molecule drug

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Neoplasms	5

Top 5 Drug Type	Count

Small molecule drug	5

Top 5 Target	Count

UNG(uracil DNA glycosylase)	1
FEN1(flap structure-specific endonuclease 1)	1
APE1(DNA-(apurinic or apyrimidinic site) lyase)	1
WRN(WRN RecQ like helicase)	1
POLH(DNA polymerase eta)	1

AbstractQuickly generating reliable hits from library screening and rapidly converting them into lead compounds, which can be verified in functional assays, is critical in early preclinical drug discovery. The expedited validation of “druggability” of targets and identification of modulators to advance to preclinical studies can significantly increase the success of drug discovery and development. Our SaXPy (“SAR by X-ray Poses Quickly”) platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or “undruggable” targets, allows (i) hit generation; (ii) mapping of protein-ligand interactions; (iii) assessment of target ligandability; (iv) discovery of novel and potential allosteric binding sites; and (v) hit-to-lead progression. These advances inform chemical tractability, downstream biology, and intellectual property. We describe here the application of SaXPy in the discovery and development of DNA Damage Response (DDR) inhibitors against DNA polymerase eta (Pol 𝝶 or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our studies resulted in the first crystal structures of these targets bound to small molecules and the discovery of novel, multiple binding sites, which we could quickly progress from hit-to-lead development and demonstrate functional activity in bioassays.Citation Format: Debanu Das, Matthew Duncton, Ashley Deacon, David Wilson III. Applying a new drug discovery platform for the discovery and development of inhibitors of DDR proteins APE1 and Pol eta [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B053.

Frontiers in OncologyQ3 · MEDICINE

Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

Q3 · MEDICINE

ArticleOA

Author: Deacon, Ashley M ; Duncton, Matthew A J ; Chang, Caleb ; Das, Debanu ; Georgiadis, Taxiarchis M ; Gao, Yang ; Wilson, David M ; Lee Luo, Christie ; Pellicena, Patricia

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.

International Journal of Molecular Sciences

A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1

Article

Author: Georgiadis, Taxiarchis M ; Sobol, Robert W ; King-Underwood, John ; Duncton, Matthew A J ; Clark, Jennifer ; Georgiadis, Millie M ; Chang, Caleb ; Jobes, David V ; Gao, Yang ; Deacon, Ashley M ; Das, Debanu ; Wilson, David M ; Pellicena, Patricia

The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPyTM (“SAR by X-ray Poses Quickly”) platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or “undruggable” targets, allows for (i) hit generation; (ii) the mapping of protein–ligand interactions; (iii) the assessment of target ligandability; (iv) the discovery of novel and potential allosteric binding sites; and (v) hit-to-lead execution. These advances inform chemical tractability and downstream biology and generate novel intellectual property. We describe here the application of SaXPy in the discovery and development of DNA damage response inhibitors against DNA polymerase eta (Pol η or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our SaXPy platform allowed us to solve the first crystal structures of these proteins bound to small molecules and to discover novel binding sites for each target.

100 Deals associated with Xpose Therapeutics, Inc.

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100 Translational Medicine associated with Xpose Therapeutics, Inc.

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Pipeline

Pipeline Snapshot as of 22 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Discovery

1

4

Preclinical

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Target POLH(XPose Therapeutics) ( POLH )	Neoplasms More	Preclinical
Target APE1(XPose Therapeutics) ( APE1 )	Neoplasms More	Preclinical
Target UDG (XPose Therapeutics) ( UNG )	Neoplasms More	Preclinical
Target FEN1 (XPose Therapeutics) ( FEN1 )	Neoplasms More	Preclinical
WRN Inhibitor(XPose Therapeutics) ( WRN )	Neoplasms More	Discovery