To outsmart aggressive cancers, scientists need a new approach. They need to turn on tumor suppressor genes and tumor evasion genes which have been deactivated by malignant cells. One of the newest approaches is using synthetic lethality — when two simultaneous genetic events result in cell death. Cells can live when one gene is lost but cannot survive the combined loss of a redundant pathway. With synthetic lethality, scientists are able to exploit this redundant pathway, often by introducing a precision-designed therapeutic.

Synthetic lethality offers new hope for treating cancers that have eluded other forms of therapy, including breast, ovarian, bladder, and pancreatic cancers with specific mutations and deletions, like BRCA (breast cancer gene) mutation and MTAP (methylthioadenosine phosphorylase) deletion. BRCA1 and BRCA2 are tumor suppressor and DNA repair genes. These genes are mutated in many cancers, including 30-40% of familial breast cancer patients and up to 80% of hereditary ovarian cancer patients. To block these genes, the synthetic lethality target is PARP, a DNA repair enzyme that can be chemically inhibited to suppress tumor growth. MTAP, another enzyme important to cell function that is deficient in many cancers, can be targeted through MAT2A (methionine adenosyltransferase 2A), an enzyme that plays an essential role in cell function and survival as the primary producer of S-adenosylmethionine (SAM). WRN (Werner Helicase), another enzyme active in DNA repair and transcription, has also been discovered as a promising synthetic lethality target for colorectal and other cancers.

In order to find new synthetic lethality targets and develop novel therapeutics, scientists are relying on the latest technologies, including CRISPR gene-editing and artificial intelligence (AI). Many big pharma companies and biotech startups are jumping into the race.

2020 was a major year for synthetic lethality plays, with numerous high-profile deals launched, including a $65m deal between Bristol Myers Squibb and Repare Therapeutics to find new synthetic lethality targets. Repare Therapeutics relies on a CRISPR platform to develop targeted cancer therapies. The company has a number of synthetic lethality-based precision oncology therapeutics in Phase 1 and 2 trials.

2020 also saw the announcement of a major deal between GSK and Ideaya Biosciences with Ideaya receiving a $100m upfront payment and other incentives to further develop its synthetic lethality programs targeting MAT2A, Pol Theta, and WRN. In March of 2022, Ideaya announced favorable clinical results in Phase 1 trials for its MAT2A inhibitor. On May 2, 2022, the company announced that the FDA granted orphan drug designation status to darovasertib, a potentially first-in-class protein kinase C or PKC inhibitor that is designed to treat a rare cancer of the eye known as uveal melanoma. The company is looking to combine darovasertib with crisotinib, a cMET inhibitor — a synthetic lethality combo — in Phase 1 and 2 clinical trials.

Tango Therapeutics raised $60m to advance its synthetic lethality program, also in 2020. It received fast-track designation from the FDA to expedite TNG908, a synthetic lethal inhibitor of the protein PRMT5 which targets cancer cells with MTAP deletion in late March.

Thanks to successful trials – reducing the risk of recurring invasive breast cancer or of second cancers or death by 42% compared to placebo — the drug Lynparza from AstraZeneca and Merck was approved in the U.S. for the treatment of patients with BRCA-mutated HER2-negative high risk breast cancer in March 2022.

GSK's synthetic lethality drug, Zejula, which treats patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who have not responded to chemotherapy and have a BRCA mutation, was approved by the FDA in April 2020. Zejula is a PARP inhibitor.

The latest synthetic lethality novel targets and therapeutics are being fast tracked using the power of AI. Just weeks apart, Insilico Medicine, a clinical-stage end-to-end AI-driven drug discovery company, announced two synthetic lethality preclinical candidates (PCCs) developed using its AI software platform. The first, announced on April 13, 2022, targets ubiquitin-specific protease 1 (USP1), an enzyme that contributes to DNA repair in cancer cells. Insilico Medicine's PCC, which is undergoing Investigational New Drug (IND) study in order to advance it to clinical trials, demonstrated promise against homologous recombination deficient-(HRD) tumors, including in BRCA-mutant cancer cells.

On May 5, 2022, Insilico announced a second AI-designed synthetic lethality PCC targeting MAT2A for MTAP-deleted cancers. This, too, is being progressed to IND-enabling studies.

Thanks to Insilico's end-to-end AI platform, PHARMA.AI, which includes novel target discovery (PandaOmics) and novel small molecule design (Chemistry42), both therapies went from target to PCC in under 12 months.

Brita Belli is the Head of PR for Insilico Medicine, a clinical-stage end-to-end artificial intelligence (AI)-driven drug discovery company. Prior to Insilico, she led communications for the Yale School of Medicine Office of Diversity, Equity and Inclusion. Her writing has been featured in the New York Times, National Geographic, MSN.com, and Alternet. She's the author of The Autism Puzzle: Connecting the Dots Between Environmental Toxins and Rising Autism Rates (Seven Stories Press) as well as a digital playbook, Elevating Women in Entrepreneurship, sponsored by JP Morgan Chase and InBIA.

Insilico Medicine, a clinical stage end-to-end artificial intelligence (AI)-driven drug discovery company, is connecting biology, chemistry, and clinical trials analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques to discover novel targets and to design novel molecular structures with desired properties. Insilico Medicine is delivering breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system (CNS) diseases and aging-related diseases.

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