NFDI4DS | UHH-SEMS - Publication Details

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur the and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, prominently hyperglycemia due inhibition wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations cryo-electron microscopy identify an allosteric network that provides explanation for how mutations favor...

10.1158/2159-8290.cd-23-0944 article EN cc-by-nc-nd Cancer Discovery 2023-11-02

Supplementary Data from First Results of Migoprotafib, a Potent and Highly Selective Src Homology-2 Domain–Containing Phosphatase 2 Inhibitor in Patients with Advanced Solid Tumors

OPENALEX - Publications

Melissa L. Johnson Beni B. Wolf Judy S. Wang Alexander Philipovskiy Geoffrey I. Shapiro and 15 more

Supplementary Tables

10.1158/1535-7163.28531532 preprint EN cc-by 2025-03-04

Data from First Results of Migoprotafib, a Potent and Highly Selective Src Homology-2 Domain–Containing Phosphatase 2 Inhibitor in Patients with Advanced Solid Tumors

OPENALEX - Publications

Melissa L. Johnson Beni B. Wolf Judy S. Wang Alexander Philipovskiy Geoffrey I. Shapiro and 15 more

<div>AbstractSrc homology-2 domain–containing phosphatase 2 promotes rat sarcoma viral oncogene homolog–MAPK signaling and tumorigenesis is a promising therapeutic target for multiple solid tumors. Migoprotafib potent highly selective Src inhibitor designed the treatment of homolog–MAPK–driven cancers, particularly in combination with other targeted agents. Here, we report first-in-human study results single-agent migoprotafib patients advanced tumor. We conducted phase Ia,...

10.1158/1535-7163.c.7702676 preprint EN 2025-03-04

Abstract CT017: Pan-mutant and isoform selective PI3Kα inhibitor, RLY-2608, demonstrates selective targeting in a first-in-human study of PIK3CA-mutant solid tumor patients, ReDiscover trial

OPENALEX - Publications

Andreas Varkaris Komal Jhaveri Cesar A. Perez Janice S. Kim Jason T. Henry and 15 more

Abstract BACKGROUND: Oncogenic activation of PI3Kα via mutation PIK3CA is the most common kinase driver event across solid tumors, particularly breast cancer (BC). Alpelisib, an orthosteric inhibitor, validated mutant-PI3Kα as a therapeutic target; however, toxicity from non-selective inhibition WT (hyperglycemia) and other PI3K isoforms limits its clinical activity. RLY-2608, novel oral allosteric designed to overcome these limitations mutant- isoform-selective inhibition. We initiated...

10.1158/1538-7445.am2023-ct017 article EN Cancer Research 2023-05-29

First-in-human global multi-center study of RLY-2608, a pan-mutant and isoform-selective PI3Kα inhibitor, as a single agent in patients with advanced solid tumors and in combination with fulvestrant in patients with advanced breast cancer.

OPENALEX - Publications

Cesar A. Perez Jason T. Henry Andreas Varkaris Vivek Subbiah Alexander I. Spira and 9 more

TPS1124 Background: Targeting constitutively active mutant kinases with selective small molecule inhibitors is a key therapeutic pillar of precision oncology. Phosphatidylinositol-4,5bisphosphate-3 kinase, catalytic subunit alpha ( PIK3CA) mutations leading to oncogenic activation PI3Kα represent the largest opportunity for this approach in solid tumors. However, there no inhibitor that targets clinic. Toxicity related non-selective inhibition WT (hyperglycemia) and other PI3K isoforms...

10.1200/jco.2022.40.16_suppl.tps1124 article EN Journal of Clinical Oncology 2022-06-01

Abstract OT3-22-01: First-in-human global multi-center study of RLY-2608, a pan mutant and isoform selective PI3Kα inhibitor, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer

OPENALEX - Publications

Andreas Varkaris Erika Hamilton Jason T. Henry Alexander I. Spira Alison M. Schram and 9 more

Abstract Background: Targeting constitutively active mutant kinases with selective small molecule inhibitors is a key therapeutic pillar of precision oncology. Phosphatidylinositol-4,5bisphosphate-3 kinase, catalytic subunit alpha (PIK3CA) mutations leading to oncogenic activation PI3Kα represent the largest opportunity for this approach in solid tumors. However, there no inhibitor that targets clinic. Toxicity related non-selective inhibition WT (hyperglycemia) and other PI3K isoforms...

10.1158/1538-7445.sabcs22-ot3-22-01 article EN Cancer Research 2023-03-01

Table S2 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Time-dependence of biochemical inhibition and mutant selectivity RLY-2608

10.1158/2159-8290.25191456.v1 preprint EN cc-by 2024-02-08

Figure S1 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Activation loop residues 937-954 are more disordered in mutant vs. wildtype PI3Kα

10.1158/2159-8290.25191483.v1 preprint EN cc-by 2024-02-08

Figure S2 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

PI3Kα KD Simulations

10.1158/2159-8290.25191480.v1 preprint DA cc-by 2024-02-08

Figure S7 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Body weight changes observed in vivo models upon treatment with RLY-2608

10.1158/2159-8290.25191465 preprint EN cc-by 2024-02-08

Figure S7 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Body weight changes observed in vivo models upon treatment with RLY-2608

10.1158/2159-8290.25191465.v1 preprint EN cc-by 2024-02-08

Data from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

<div>AbstractPIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur the and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, prominently hyperglycemia due inhibition wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations cryo-electron microscopy identify an allosteric network...

10.1158/2159-8290.c.7065332.v1 preprint EN 2024-02-08

Figure S3 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Binding kinetics and potency of [2] towards PI3Kα

10.1158/2159-8290.25191477 preprint EN cc-by 2024-02-08

Figure S4 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Binding kinetics and potency of [1] towards tailless PI3Kα

10.1158/2159-8290.25191474.v1 preprint EN cc-by 2024-02-08

Supplemental Text from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Synthesis of mutant-selective allosteric PI3Kα inhibitors

10.1158/2159-8290.25191462 preprint EN cc-by 2024-02-08

Figure S1 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Activation loop residues 937-954 are more disordered in mutant vs. wildtype PI3Kα

10.1158/2159-8290.25191483 preprint EN cc-by 2024-02-08

Table S1 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

In vitro kinome profile of RLY-2608. RLY-2608 was tested at a concentration 10 µM by SelectScreen (ThermoFisher Scientific)

10.1158/2159-8290.25191459 preprint EN cc-by 2024-02-08

Figure S2 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

PI3Kα KD Simulations

10.1158/2159-8290.25191480 preprint DA cc-by 2024-02-08

Figure S6 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Varied levels of PI3Kα-dependency across cell lines

10.1158/2159-8290.25191468 preprint EN cc-by 2024-02-08

Table S1 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

In vitro kinome profile of RLY-2608. RLY-2608 was tested at a concentration 10 µM by SelectScreen (ThermoFisher Scientific)

10.1158/2159-8290.25191459.v1 preprint EN cc-by 2024-02-08

Table S2 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Time-dependence of biochemical inhibition and mutant selectivity RLY-2608

10.1158/2159-8290.25191456 preprint EN cc-by 2024-02-08

Figure S5 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Isoform selectivity of RLY-2608

10.1158/2159-8290.25191471.v1 preprint EN cc-by 2024-02-08

Figure S4 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Binding kinetics and potency of [1] towards tailless PI3Kα

10.1158/2159-8290.25191474 preprint EN cc-by 2024-02-08

Figure S6 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Varied levels of PI3Kα-dependency across cell lines

10.1158/2159-8290.25191468.v1 preprint EN cc-by 2024-02-08

Figure S5 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

OPENALEX - Publications

Andreas Varkaris Ermira Pazolli Hakan Günaydin Qi Wang Levi Pierce and 47 more

Isoform selectivity of RLY-2608

10.1158/2159-8290.25191471 preprint EN cc-by 2024-02-08

Tamieka L. Hunter