Innovative drugs work as a “black mark”.
Until recently, KRAS was considered one of the most difficult targets in oncology. Mutations in this protein are the basis of a number of the most deadly forms of cancer, but decades of trying to create a cure against it again and again relied on the same problem: protein is too inconvenient to attack, and rare successes quickly negate the stability of the tumor. The picture has now begun to change. The researchers approached KRAS from several sides, and the direction that has been associated with disappointments for too long had the first truly encouraging results.
The main change is not associated with one magic molecule, but with a whole set of new strategies. The first clinical study of the drug, which not just blocks one of the mutant forms of KRAS, but causes the cell to destroy this protein, has already shown signs of efficacy. In parallel, there are four large clinical trials of another drug, which suppresses several mutant variants of KRAS and related proteins. The results of the first of these tests may appear in the coming months.
Overestimate what is happening, however, no one is in a hurry. Researchers directly say that none of the current approaches in itself is unlikely to be a complete cure. The logic is now another: not to look for one blow, which will finally turn off the tumor, but to collect combinations, from which the cancer will be more difficult to turn off. We are talking about schemes where different drugs either complement each other, or block the pathways of waste, which tumor cells usually use after the first successful blow to KRAS.
The reason for such cautious optimism is clear if you remember why KRAS in general remained almost inaccessible for so long. Protein belongs to the RAS family, which plays an important role in cell growth and division. Some mutations in KRAS fix it in a constant active state. Normally, growth signals should be turned on and off as needed, and here the system seems to get stuck in the position on. The cell continues to receive a team for reproduction, and it is this continuous stimulation that becomes one of the foundations of tumor growth.
On paper, the target looked almost perfect. If the protein is returned to an inactive state, the tumor would lose one of the key engines. In practice, everything turned out to be much more complicated. The surface of KRAS is relatively smooth, without comfortable pockets, for which medicinal molecules usually cling to. For drug developers, this is an almost nightmare scenario: the usual chemical logic works worse, and to choose a compound that will not just contact the protein, but will make it reliably and selectively, it turns out to be much more difficult.
Even when chemists managed to find molecules capable of binding to the mutant KRAS and suppress its activity, the victory turned out to be short. The tumors began to adapt. Sustainability developed in almost every patient, and it quickly became clear that simple inhibition did not solve the problem for a long time. Some tumors acquired additional mutations in KRAS itself, because of which the drug worked worse. Others included bypass cellular processes that could partially compensate for the loss of KRAS function. As a result, the effect weakened, and the tumor again found a way to growth.
From this problem, one of the most interesting current ideas has grown: not to try to temporarily block the mutant protein, but to remove it from the whole cell. So there were degrades, that is, molecules that do not work as ordinary inhibitors. Their task is to contact KRAS and at the same time bring it to another protein, E3-ubiquitinliga. After that, the cellular mechanism of protein marking as debris is started. KRAS receives a chemical label, according to which the protein recycling system recognizes it as an unnecessary element, splits and removes.
From a scientific point of view, the move is very beautiful, but technically it is much more complicated than it may seem in a brief description. It is not easy to easily get in touch of one molecule with another. It is necessary to make several components come together in the desired geometry, at the right moment and with the necessary stability, so that the cell really sends the target for destruction. In some conditions, the protein can be destroyed, in others the entire scheme falls apart and does not give the desired result. Therefore, the development of degraders requires almost acrobatics from chemists at the level of molecular engineering.
The more interesting is that the first clinical program for degradation of one of the forms of mutant KRAS has already begun to show signs of success. For this direction, the very fact that the idea has gone beyond the beautiful biochemical design and began to work in a real clinical context. At the same time, studies of another class препаратовof drugs that act wider and beat several mutant forms of KRAS and related proteins are continuing at once. These approaches have different logic, and that is why they can be especially valuable in combination: one weakens the key protein, the other does not allow the tumor to easily switch to close survival mechanisms.
Perhaps the main change in the history of KRAS now is not that the problem has already been solved, but that the field has ceased to be a dead end. Until recently, the conversation about KRAS was more often ending with a list of reasons why it is almost impossible to create a working drug against it. Now the discussion has shifted to another point.
Until recently, KRAS was considered one of the most difficult targets in oncology. Mutations in this protein are the basis of a number of the most deadly forms of cancer, but decades of trying to create a cure against it again and again relied on the same problem: protein is too inconvenient to attack, and rare successes quickly negate the stability of the tumor. The picture has now begun to change. The researchers approached KRAS from several sides, and the direction that has been associated with disappointments for too long had the first truly encouraging results.
The main change is not associated with one magic molecule, but with a whole set of new strategies. The first clinical study of the drug, which not just blocks one of the mutant forms of KRAS, but causes the cell to destroy this protein, has already shown signs of efficacy. In parallel, there are four large clinical trials of another drug, which suppresses several mutant variants of KRAS and related proteins. The results of the first of these tests may appear in the coming months.
Overestimate what is happening, however, no one is in a hurry. Researchers directly say that none of the current approaches in itself is unlikely to be a complete cure. The logic is now another: not to look for one blow, which will finally turn off the tumor, but to collect combinations, from which the cancer will be more difficult to turn off. We are talking about schemes where different drugs either complement each other, or block the pathways of waste, which tumor cells usually use after the first successful blow to KRAS.
The reason for such cautious optimism is clear if you remember why KRAS in general remained almost inaccessible for so long. Protein belongs to the RAS family, which plays an important role in cell growth and division. Some mutations in KRAS fix it in a constant active state. Normally, growth signals should be turned on and off as needed, and here the system seems to get stuck in the position on. The cell continues to receive a team for reproduction, and it is this continuous stimulation that becomes one of the foundations of tumor growth.
On paper, the target looked almost perfect. If the protein is returned to an inactive state, the tumor would lose one of the key engines. In practice, everything turned out to be much more complicated. The surface of KRAS is relatively smooth, without comfortable pockets, for which medicinal molecules usually cling to. For drug developers, this is an almost nightmare scenario: the usual chemical logic works worse, and to choose a compound that will not just contact the protein, but will make it reliably and selectively, it turns out to be much more difficult.
Even when chemists managed to find molecules capable of binding to the mutant KRAS and suppress its activity, the victory turned out to be short. The tumors began to adapt. Sustainability developed in almost every patient, and it quickly became clear that simple inhibition did not solve the problem for a long time. Some tumors acquired additional mutations in KRAS itself, because of which the drug worked worse. Others included bypass cellular processes that could partially compensate for the loss of KRAS function. As a result, the effect weakened, and the tumor again found a way to growth.
From this problem, one of the most interesting current ideas has grown: not to try to temporarily block the mutant protein, but to remove it from the whole cell. So there were degrades, that is, molecules that do not work as ordinary inhibitors. Their task is to contact KRAS and at the same time bring it to another protein, E3-ubiquitinliga. After that, the cellular mechanism of protein marking as debris is started. KRAS receives a chemical label, according to which the protein recycling system recognizes it as an unnecessary element, splits and removes.
From a scientific point of view, the move is very beautiful, but technically it is much more complicated than it may seem in a brief description. It is not easy to easily get in touch of one molecule with another. It is necessary to make several components come together in the desired geometry, at the right moment and with the necessary stability, so that the cell really sends the target for destruction. In some conditions, the protein can be destroyed, in others the entire scheme falls apart and does not give the desired result. Therefore, the development of degraders requires almost acrobatics from chemists at the level of molecular engineering.
The more interesting is that the first clinical program for degradation of one of the forms of mutant KRAS has already begun to show signs of success. For this direction, the very fact that the idea has gone beyond the beautiful biochemical design and began to work in a real clinical context. At the same time, studies of another class препаратовof drugs that act wider and beat several mutant forms of KRAS and related proteins are continuing at once. These approaches have different logic, and that is why they can be especially valuable in combination: one weakens the key protein, the other does not allow the tumor to easily switch to close survival mechanisms.
Perhaps the main change in the history of KRAS now is not that the problem has already been solved, but that the field has ceased to be a dead end. Until recently, the conversation about KRAS was more often ending with a list of reasons why it is almost impossible to create a working drug against it. Now the discussion has shifted to another point.
