# Development of Targeted Damaging Agents for the Treatment of Drug-Resistant Gliomas

> **NIH NIH R44** · MODIFI BIOSCIENCES INC · 2023 · $1,107,901

## Abstract

PROJECT SUMMARY
Loss of O6-methylguanine methyltransferase (MGMT) expression is common in cancers and confers sensitivity
to DNA alkylators, such as temozolomide (TMZ). Epigenetic silencing of MGMT via promoter hypermethylation
is found in ~50% of glioblastomas (GBMs), and in most lower grade gliomas with isocitrate dehydrogenase-1/2
(IDH1/2) mutations. MGMT is also silenced in other cancers, including up to 40% of colon cancers, 35% of small
cell lung cancers, and 25% of non-small cell lung cancers. In cells that lack MGMT expression (termed MGMT-cells), TMZ-derived O6-methylguanine (O6MeG) lesions mispair with thymine, during DNA replication, due to
altered hydrogen base pairing, leading to activation of the mismatch repair pathway (MMR). MMR attempts to
repair these lesions by resecting the newly synthesized strand, but thymine once again is inserted opposite of
O6MeG. This reinsertion again triggers MMR, leading to iterative “futile cycles” of DNA repair and ultimately
apoptosis. Clinically, MGMT promoter demethylation is rare, whereas MMR mutations occur frequently as a
dominant mechanism of resistance to TMZ in many tumor types. Because MGMT silencing is found in many
cancers, DNA lesions that overcome the MMR resistance (while still being resolvable by MGMT, so as to
maintain a therapeutic index (TI)) will have a broad impact. Furthermore, as this biomarker persists even in the
treatment-refractory setting (i.e., in the context of MMR defects), we argue that loss of MGMT expression has
not been fully exploited for therapeutic gain. Based on the findings presented above, we seek to develop a new
class of agents discovered in the laboratory of Drs. Ranjit Bindra and Seth Herzon that generate O6MeG lesions 
that are susceptible to MGMT removal (“MGMT dependent”) in healthy cells, but which can overcome MMR 
resistance (“MMR independent”). To this end, Drs. Bindra and Herzon have co-founded KL50 Therapeutics, LLC,
and their studies lead to the identification of KL50, a novel alkylation agent that is more active against MMR- cell
lines than MMR+ cell lines, while retaining MGMT resolvability. This molecule demonstrates exquisite sensitivity 
in MGMT-deficient cells independent of MMR status, with negligible activity in MGMT-proficient cells, and has a 
TI approximately 30 times greater than TMZ. Building on these achievements, in this fast-track SBIR project, we 
propose to conduct lead optimization to improve central nervous system (CNS) penetration, identify a collection 
of small molecules with in vivo efficacy in mouse models of high-grade gliomas (HGG), and further develop these
compounds for use in a Phase 1 clinical trial. These MGMT dependent–MMR independent alkylating agents are 
anticipated to possess the positive attributes of TMZ, while circumventing the unavoidable MMR loss mediated 
resistance mechanism and, thereby, have a major impact on the way we treat GBMs and other tumors lacking
MGMT. These molecules could represent a parad...

## Key facts

- **NIH application ID:** 10812561
- **Project number:** 4R44CA271994-02
- **Recipient organization:** MODIFI BIOSCIENCES INC
- **Principal Investigator:** Gerald Francis Vovis
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,107,901
- **Award type:** 4N
- **Project period:** 2022-09-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812561

## Citation

> US National Institutes of Health, RePORTER application 10812561, Development of Targeted Damaging Agents for the Treatment of Drug-Resistant Gliomas (4R44CA271994-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10812561. Licensed CC0.

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