Anticancer Target Combinations: Network-Informed Signaling-Based Approach to Discovery DOI Creative Commons
Bengi Ruken Yavuz, Hyunbum Jang, Ruth Nussinov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract While anticancer drug discovery has seen dramatic innovations and successes, sequential single therapies are time-limited by resistance, combinatorial strategies have been lagging. The number of possible combinations is vast. To select the oncologist requires knowledge optimal combination proteins to co-target. Currently, that considers primarily from empirical observations clinical praxis. Our aim develop a signaling-based method discover for co-target with combinations, test it on available, patient-derived data. temper expected resistance regimen, we offer concept-based stratified pipeline aimed at selecting co-targets combinations. strategy unique in its selection being based signaling pathways. This significant since cancer, commonly bypasses blocked wielding alternative, or complementary, routes execute cell proliferation. network-informed approach harnesses advanced network concepts metrics, our compiled, tissue-specific co-existing mutations. Co-existing driver mutations common resistance. Thus, mimic cancer counter scenarios, seeks when targeted can shut off cancer’s modus operandi . That is, parallel complementary pathways would be blocked. Rotating through could further lessen emerging We applied breast colorectal ESR1 | PIK3CA BRAF subnetworks. Consistently, results suggest co-targeting ESR1|PIK3CA subnetwork an alpelisib-LJM716 combination. In they alpelisib, cetuximab, encorafenib Collectively, pipeline’s promising, validated patient-based xenografts. GRAPHICAL ABSTRACT

Language: Английский

ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events DOI Creative Commons
Clil Regev, Hyunbum Jang, Ruth Nussinov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

Abstract ERK, a coveted proliferation drug target, is pivotal kinase in the Ras/ERK signaling cascade. Despite this, crucial questions about its activation have not been fully explored on foundational, conformational level. Such include (i) Why ERK’s demands dual phosphorylation ; (ii) What role of each site loop and (iii) Exactly how (ordered) steps affect ensembles , their propensities restriction to narrower range favoring catalytic action . Here we used explicit molecular dynamics simulations study stability changes different stages along process. The initial monophosphorylation event elongates enable successive phosphorylations, which reintroduce stability/compactness through newly formed salt bridges. interactions by are site-dependent, with threonine’s presenting stronger electrostatic compared tyrosine’s. Dual phosphorylated ERKs revealed compact structure allows HRD motif stabilize ATP. We further observe that hinge homodimerization binding responded tri-state code based solely degree (unphosphorylated, monophosphorylated, phosphorylated) loop, confirming can allosterically influence distant regions. Last, our findings indicate threonine as second step necessary for ERK become effectively activated depends order. Collectively, offer allosteric explain why order crucial.

Language: Английский

Citations

0
ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events DOI
Clil Regev, Hyunbum Jang, Ruth Nussinov

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169130 - 169130

Published: April 1, 2025

Language: Английский

Citations

0
Anticancer Target Combinations: Network-Informed Signaling-Based Approach to Discovery DOI Creative Commons
Bengi Ruken Yavuz, Hyunbum Jang, Ruth Nussinov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract While anticancer drug discovery has seen dramatic innovations and successes, sequential single therapies are time-limited by resistance, combinatorial strategies have been lagging. The number of possible combinations is vast. To select the oncologist requires knowledge optimal combination proteins to co-target. Currently, that considers primarily from empirical observations clinical praxis. Our aim develop a signaling-based method discover for co-target with combinations, test it on available, patient-derived data. temper expected resistance regimen, we offer concept-based stratified pipeline aimed at selecting co-targets combinations. strategy unique in its selection being based signaling pathways. This significant since cancer, commonly bypasses blocked wielding alternative, or complementary, routes execute cell proliferation. network-informed approach harnesses advanced network concepts metrics, our compiled, tissue-specific co-existing mutations. Co-existing driver mutations common resistance. Thus, mimic cancer counter scenarios, seeks when targeted can shut off cancer’s modus operandi . That is, parallel complementary pathways would be blocked. Rotating through could further lessen emerging We applied breast colorectal ESR1 | PIK3CA BRAF subnetworks. Consistently, results suggest co-targeting ESR1|PIK3CA subnetwork an alpelisib-LJM716 combination. In they alpelisib, cetuximab, encorafenib Collectively, pipeline’s promising, validated patient-based xenografts. GRAPHICAL ABSTRACT

Language: Английский

Citations

0