Relay Therapeutics Announces Preclinical Data that Support RLY-2608 as the First Known Allosteric Pan-Mutant Selective Inhibitor of PI3K RLY-2608 preferentially binds mutant PI3K at a novel allosteric site discovered by

Relay Therapeutics Announces Preclinical Data that Support

RLY-2608 as the First Known Allosteric Pan-Mutant Selective Inhibitor of PI3K

RLY-2608 preferentially binds mutant PI3K at a novel allosteric site

discovered by the Dynamo platform

Preclinically, achieved tumor

regressions in vivo with significantly reduced impact on glucose metabolism compared to active site inhibitors

RLY-2608 s pan-mutant inhibition has the potential to address over 100,000 patients per year in the U.S.

Cambridge, MA October 07, 2021 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug

discovery process by combining leading-edge computational and experimental technologies, today shared preclinical data at the virtual AACR-NCI-EORTC Molecular Targets

Conference for RLY-2608, the first allosteric, pan-mutant (H1047X, E542X and E545X) and isoform-selective PI3K inhibitor.

The data presented at the conference show that in preclinical models, RLY-2608 preferentially binds mutant

PI3K at a novel allosteric site discovered by the Dynamo platform. Scientists at Relay Therapeutics solved the full-length structure of PI3K , performed long time-scale

molecular dynamic simulations to elucidate differences in motion between wild-type (WT) and mutant PI3K , and leveraged these insights to enable the design of RLY-2608. In biochemical and cellular assays,

RLY-2608 inhibited the three major classes of PI3K oncogenic mutations (H1047X, E542X and E545X) while sparing WT PI3K . The data further suggest that

RLY-2608 is also highly selective against other PI3K family members and exquisitely selective across the kinome. The data suggest that projected clinically relevant doses of

RLY-2608 achieved tumor regression in PIK3CA mutant in vivo xenograft models representing H1047R and E545K mutations with significantly reduced impact on glucose metabolism compared to non-mutant selective active site inhibitors. In higher species, dosing of RLY-2608 resulted in exposures exceeding 90% inhibition of mutant PI3K in cells without

resulting in elevated glucose levels or histopathological changes associated with dysregulation of glucose metabolism that are seen with non-mutant selective inhibitors.

These results support advancement of RLY-2608 into clinical development as a differentiated mechanism of mutant

PI3K inhibition with the first-in-human study anticipated to start in the first half of 2022. RLY-2608 is the lead program

of multiple preclinical efforts at Relay Therapeutics to discover and develop mutant selective inhibitors of PI3K .

RLY-2608 has the potential to address over 100,000 patients per year in the United States, one of the largest patient

populations for a precision oncology medicine. Selectivity for all three mutation hot spots (H1047X, E542X and E545X) has the potential to effectively double the addressable patient population compared to selectivity for only H1047X.

The data shared today provide another proof point that we re developing what we believe to be the first known

pan-mutant selective allosteric inhibitor of PI3K , said Don Bergstrom, M.D., Ph.D., executive vice president of R&D at Relay Therapeutics. We believe

RLY-2608 has the potential to address a significant unmet medical need in a large population and have validated our approach for developing mutant selective inhibitors of PI3K . RLY-2608 is only the start of our PI3K efforts, and by leveraging our Dynamo platform, we plan to build a franchise around this target for the

Conference Call Information

Relay Therapeutics will host a live webcast and conference call tomorrow, October 8, beginning at 12:30 pm E.T. to discuss the results of this

presentation and the RLY-4008 presentation tomorrow. To access the live call, please dial (833) 540-1168 (domestic) or (929)

517-0359 (international) and refer to conference ID 4657916. A webcast of the conference call will be available under News and Presentations in the Media & Investors section of Relay

Therapeutics website at http://ir.relaytx.com. The archived webcast will be available on Relay Therapeutics website approximately two hours after the conference call and will be available for 30 days following the call.

The data presentation from the AACR-NCI-EORTC Molecular Targets Conference is

also available on the Relay Therapeutics website under Publications/Presentations at https://relaytx.com/pipeline/.

RLY-2608 is the lead program of multiple preclinical efforts to

discover and develop mutant selective inhibitors of PI3K . PI3K is the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 13% of patients with solid tumors. Traditionally, the development of

PI3K inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus WT PI3K and

off-isoform activity. Toxicity related to inhibition of WT PI3K and other PI3K isoforms results in sub-optimal inhibition of mutant PI3K with reductions in

dose intensity and frequent discontinuation. The Dynamo platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant (H1047X, E542X and E545X), and isoform-selective PI3K inhibitor designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM

structure of PI3K , performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3K , and leveraged these insights to support the design of RLY-2608. RLY-2608 is on path to initiate a first-in-human clinical trial in the first half of

2022, subject to submission of an investigational new drug application and acceptance by the FDA.

About Relay Therapeutics

Relay Therapeutics (Nasdaq: RLAY) is a clinical-stage precision medicines company transforming the drug discovery process by combining leading-edge

computational and experimental technologies with the goal of bringing life-changing therapies to patients. Relay Therapeutics is the first of a new breed of biotech created at the intersection of disparate technologies. Relay Therapeutics

Dynamo platform integrates an array of leading-edge computational and experimental approaches designed to drug protein targets that have previously been intractable. Relay Therapeutics

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including,

without limitation, implied and express statements regarding: Relay Therapeutics strategy, business plans and focus; the progress and timing of updates on the clinical development of the programs across Relay Therapeutics portfolio,

including the timing of initiation of a first-in-human clinical trial of RLY-2608; potential therapeutic effects and anticipated

clinical benefits of RLY-2608; Relay Therapeutics plans to build a franchise around PI3K ; the potential target patient population of RLY-2608; and whether

preclinical results of RLY-2608 will be predictive of future clinical trials of RLY-2608. The words may, might, will,

could, would, should, expect, plan, anticipate, intend, believe, expect, estimate, seek, predict,

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including, without limitation, risks associated with: the impact of COVID-19 on countries or regions in which Relay Therapeutics has operations or does business, as well as on the timing and anticipated

results of its clinical trials, strategy and future operations; the delay of any current or planned clinical trials or the development of Relay Therapeutics drug candidates; the risk that the results of its clinical trials may

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